Compositions of (-)-17-(cyclobutylmethyl)morphinan-3,14-diol

ABSTRACT

The present invention is directed to oral, therapeutically effective modified release pharmaceutical compositions of (−)-17-(cyclobutylmethyl)morphinan-3,14-diol and it pharmaceutically acceptable salts and the use thereof, including delayed onset and extended release dosage forms. The present invention is also directed at modified release dosage forms of oral (−)-17-(cyclobutylmethyl)morphinan-3,14-diol which provide robust efficacy and reduced potential for abuse and misuse.

This application is a §371 filing corresponding to PCT/US2011/058690,filed 31 Oct. 2011, which is entitled to priority to the applicant'sU.S. provisional application No. 61/408,544, filed Oct. 29, 2010 whichis herein incorporated in its entirety for all purposes.

FIELD OF THE INVENTION

The present invention is directed to oral, therapeutically effectivemodified release pharmaceutical compositions of(−)-17-(cyclobutylmethyl)morphinan-3,14-diol and it pharmaceuticallyacceptable salts and the use thereof, including delayed onset andextended release dosage forms. The present invention is also directed atmodified release dosage forms of oral(−)-17-(cyclobutylmethyl)morphinan-3,14-diol which provide robustefficacy and reduced potential for abuse and misuse.

BACKGROUND TO THE INVENTION

While drugs are administered by a wide variety of routes and methods,including oral, oro-transmucosal, buccal, sublingual, via NG-tubes,rectal, intranasal, inhalational, topical, transdermal, intravenous,subcutaneous, intramuscular, epidural and intrathecal, the oral route isby far the most preferred route for most patients and medical settings.

The strong preference and universal acceptance of the oral route includesimplicity of drug administration, patient convenience, lower drugcosts, and reduced complexity of manufacturing, suitability for repeatedand chronic administration and, in many cases, reliable therapeuticeffect.

In some cases, drugs need to be administered by a non-oral route. Amongthe reasons for the use of non-oral routes are lack of therapeuticeffect, lack of a consistent, reliable or robust effects, the need forrapid onset of effect, contraindications to oral drug administration,reduced safety by the oral route and the lack of availability of theoral route (for example due to GI obstruction, nausea, vomiting, GIobstruction, obtundation or coma).

Over the past several decades, there have been extensive research,development and commercialization efforts to advance alternatives toorally ingested drug administration, including oro-transmucosal, buccal,sublingual, intranasal, inhalational, topical, transdermal, intravenous,subcutaneous, intramuscular, epidural, intrathecal and transdermalroutes. Although there have been remarkable advances in alternatives toorally ingested drugs, the oral route continues to be the preferredroute of drug administration, particularly for chronic conditions whichfrequently require around thr clock amelioration of symptoms.

In many cases, the prediction of absent or significantly poortherapeutic outcomes by the oral route has led to the abandonment of itsevaluation through oral ingestion. Such drugs are frequently being usedonly by a non-oral route (e.g., parenteral route, intranasal ortransdermal).

(−)17-(Cyclobutylmethyl)morphinan-3,14-diol (Butorphanol) acts as apartial agonist at μ-opioid receptors and a pure agonist at κ-opioidreceptors, with preponderantly antagonist activity at the δ-opioidreceptor (Commiskey s, et al, J Pharmacol Sci 2005; 98; 109-116). Itssynthesis was first reported in 1973 and has been commercially availablein the USA as a parenteral formulation since 1978. It was introduced inthe U.S. in parenteral form in 1978 and intranasal form in 1991(Stadol®). Butorphanol is an infrequently utilized analgesic. Its use iswidely relegated to the treatment of acute, self-limiting pain (e.g.,migraine, postsurgical pain) where dosing may range from a single doseto a few days of therapy. Butorphanol is almost never used for thetreatment of chronic pain for a variety of reasons, including theabsence of an oral formulation, the occurrence of sedation, dizzinessand psychotomimemtic reactions, the latter attributed to its kappaopioid receptor agonism. Misuse, abuse, addiction and diversion havebeen reported in humans. Side effects due to kappa opioid receptoragonism generally increase with repeated administration, particularly toindividuals with comorbidities.

There are no orally available immediate release formulations ofbutorphanol for the prevention or treatment of any human ailments. Untilnow, butorphanol's high incidence of side effects has reduced any desireto develop an oral formulation, which is particularly suited to thetreatment of chronic conditions (e.g., chronic pain). In addition, thedevelopment and commercialization of oral butorphanol has been impededby the widely reported poor oral bioavailability. For this reason,pharmaceutical companies have made efforts to develop alternativenon-invasive methods of delivering butorphanol into systemiccirculation. Foremost among these methods is the intranasal delivery ofbutorphanol (Stadol®) for the treatment of pain.

Similarly, there are no orally available formulations of modifiedrelease or extended release butorphanol. To the applicant's knowledge,no local, state, national or international guidelines, professionalsociety or expert guidelines recommend the use of butorphanol by theoral route in any form (e.g., immediate release form or modified releaseform), either as a single entity or in combination with other drugs. Inaddition, even when patients have a suboptimal safety or efficacyresponse to other opioids, there are no recommendations that butorphanolby the oral route should be among the list of alternatives to beconsidered (e.g., second or third line therapeutic options). Indeed,even with the commercially intranasal butorphanol, there are no local,state, national or international guidelines, professional society orexpert guidelines recommending its use for the treatment of chronic pain

There is a need for oral pharmaceutical compositions of butorphanolwhich are safe and therapeutically effective.

There is also a need for oral pharmaceutical compositions of butorphanolwhich have a reduced potential for abuse. Although butorphanol has lowerrisk of abuse, it does carry a real risk of drug addiction, drugdiversion and drug abuse. Reinforcing properties and physical dependencehas been demonstrated with butorphanol in experimental models.Unfortunately, when given orally to recreational drug users or addicts,all commercially available immediate release and extended releaseopioids produce measurable euphoric or psychic effects soon afteradministration, usually within 15 to 120 minutes. Importantly,recreational opioid users, opioid addicts and patients taking opioidsfor therapeutic purposes may report different psychic experiences fromthe same dose of an opioid. Patients taking opioids for therapeuticpurposes usually desire the intended benefit (e.g., pain relief) butbemoan the mood altering effects, which may be dysphoric, whilerecreational opioid users and opioid addicts welcome such mood alteringeffects. The applicant has found a novel way to deter or minimize theabuse of oral butorphanol among recreational drug users and drug addictsby minimizing the euphoric or psychic effects of the dosage form.

To the applicant's knowledge, (i) the therapeutic benefit of orallyingested butorphanol in modified release form has heretofore not beennot been tested or established for any medical condition, includingpain, cough, pruritus, dyspnea and other opioid responsive disorders;(ii) no orally ingested controlled release formulations of butorphanolhave been has heretofore been developed or commercialized; and (iii) noorally ingested modified release, duodenal release, jejunal release,ileal release, ileo-colonic release, or colonic release formulations ofbutorphanol have been has heretofore been developed or commercialized.

The applicant has surprisingly discovered that that butorphanoldeposited, delivered or made bioavailable distal to stomach, preferablydistal to the duodenum, and more preferably, distal to the jejunum orileum provides significantly more robust therapeutic effects thanbutorphanol deposited, delivered or made bioavailable proximal to theforegoing anatomic region (e.g., as applicable, proximal to the stomach,duodenum, jejunum or ileum).

The applicant has surprisingly discovered that that butorphanoldeposited, delivered or made bioavailable distal to stomach, preferablydistal to the duodenum, and more preferably, distal to the jejunum orileum provides significantly reduced side effects than butorphanoldeposited, delivered or made bioavailable proximal to the foregoinganatomic region (e.g., as applicable, proximal to the stomach, duodenum,jejunum or ileum).

The applicant has surprisingly discovered that that butorphanoldeposited, delivered or made bioavailable distal to stomach, preferablydistal to the duodenum, and more preferably, distal to the jejunum orileum provides significantly reduced psychotomimetic side effects thanbutorphanol deposited, delivered or made bioavailable proximal to theforegoing anatomic region (e.g., as applicable, proximal to the stomach,duodenum, jejunum or ileum).

The applicant has surprisingly discovered that that butorphanoldeposited, delivered or made bioavailable distal to stomach, preferablydistal to the duodenum, and more preferably, distal to the jejunum orileum reduces the likability and abuse potential of the dosage form thanbutorphanol deposited, delivered or made bioavailable proximal to theforegoing anatomic region (e.g., as applicable, proximal to the stomach,duodenum, jejunum or ileum).

Butorphanol may be given by the intranasal route. However, intranasaladministration has a number of disadvantages, including: (i) the maximumvolume and dose of drug that can be delivered by this route ofadministration, particularly with available formulations; (ii) patientresistance with intranasal administration for systemic therapy,particularly with repeated around the clock dosing; (iii) an increasedrisk of drug diversion and drug abuse, including intravenous use withliquid forms of abusable drugs; (iv) inability to readily provideprolonged duration of therapy, for example, in extended release dosageforms; (v) lack of dose proportional increases in bioavailability over awide range of doses and particularly at high doses, thereby limitingclinical utility; (vi) a high peak concentration of butorphanol, whichcan produce various opioid side effects such as nausea, drowsiness,dizziness and (acute) cognitive impairment.

The dosage form of the invention also provides modified releasepharmaceutical compositions and methods of use to improve treatmentcompliance and to deter episodic, occasional, or intermittent use insubjects requiring chronic butorphanol therapy around the clock or on atime contingent basis by rendering the dosage form therapeuticallyineffective or suboptimally effective when taken episodically,intermittently, or occasionally.

The dosage form of the invention also provides pharmaceuticalcompositions and methods to deter the abuse and misuse of the dosageform by recreational drug users of opioids and opioid addicts byrendering the dosage form devoid of or substantially devoid of euphoria,pleasurable, drug liking or other mood alerting effects when taken on anas needed basis.

The oral route of administration is the most widely used and most widelypreferred method of drug administration. It is simple, reliable andreadily accessible. Under most conditions of use, particularly outsidethe hospital setting, it is the recommended method of drugadministration. Even in settings of skilled nursing care, where thereare resources to initiate and manage parenteral therapy, the goal is torapidly transition patients from parenteral medications to oralmedications. Some generally cited exceptions to the use of the oralroute include: (i) drugs with poor oral bioavailability; (ii) drugsrequiring a rapid onset of effect; (iii) where venous access alreadyexists (e.g., in the pen-operative or intensive care setting); (iii)where the oral route provides unreliable or inconsistent clinicaleffects. Therapeutic administration of butorphanol in modified release(e.g., controlled release or delayed onset), duodenal release, jejunalrelease, ileal release, ileo-colonic release, and colonic release dosageforms has either not been practiced or has been dismissed as unreliableor clinically unacceptable for some of the reasons noted above.

There is a need oral formulations of butorphanol that aretherapeutically efficient and that can provide modified release of thebutorphanol (e.g, delayed onset, extended release; delayed onset,duodenal delivery; delayed onset, jejunal delivery; delayed onset, ilealdelivery; delayed onset, ileo-colonic delivery and delayed onset,colonic delivery).

The applicant has demonstrated for the first time that oraladministration of butorphanol in a dosage form that models extendedrelease of butorphanol provides robust therapeutic effects.

The applicant has demonstrated for the first time that oraladministration of butorphanol in a dosage form that that models delayedonset, ileo-colonic delivery provides robust therapeutic effects andthat this therapeutic effect is more robust than following oralimmediate release of butorphanol.

There is therefore a need for new modified release oral pharmaceuticalcompositions of butorphanol and methods for the treatment of pain,cough, pruritus, dyspnea and other butorphanol responsive medicalconditions through targeted gastrointestinal delivery, availability,release, disintegration, dissolution.

Chronic butorphanol therapy can produce a variety of side effects,including drowsiness, dizziness, nausea, vomiting, constipation, psychiceffects, mood alteration and cognitive impairment. In subjects under thecare of physicians who are highly experienced in pain management in thecontrolled setting of a clinical trial (where treatment dropout ratesshould be low), approximately 20 to 40% of subjects discontinuetreatment within a few days to a few weeks of initiation of opioidtherapy due to side effects. Even after a single dose, intranasalbutorphanol produces significant side effects. After intranasaladministration of 1 mg or 2 mg butorphanol, side effects included nausea(38%; 46%), vomiting (17%; 17%), dizziness (46%; 58%) and headache (46%;29%) and oxygen desaturation (3%; 3%). An additional frequently observedside effect of intranasal butorphanol is bad taste in the mouth or theback of throat, and an unpleasant taste immediately after taking theintranasal dose.

For the management of severe pain, the U.S. prescribing information forintranasal butorphanol (Stadol®) provides the option of a 2 mg initialdose (1 mg in each nostril), but requires that this be given only tosubjects who “will be able to remain recumbent in the event drowsinessor dizziness occurs”. Therefore, side effects are a substantialdeterrent to initiating opioid therapy and they add to patient sufferingand the cost of therapy (e.g., drugs to treat the side effects,additional physician visits, etc). There is a need for therapeuticallyeffective formulations of butorphanol which have lower side effects.

Although butorphanol has a mean half-life of about 5 hours, it providesa surprisingly short duration of action following intranasaladministration. In a randomized, controlled clinical trial in subjectswith acute postsurgical pain receiving the recommended initial of 1 mgintranasal dose of butorphanol, the duration of analgesic effect (asmeasured by the median time to requesting rescue analgesia) was lessthan 2 hours. Surprisingly, the duration of analgesic effect in subjectsreceiving double this dose (2 mg) was also than 2 hours and notsignificantly different from the 1 mg dose. Even more surprising, about90% of subjects receiving the usual 1 mg intranasal dose and about 80%of subjects receiving the 2 mg dose required rescue analgesia during thefirst 6 hours of observation.

There is therefore a need for new pharmaceutical compositions andmethods for subjects in need of butorphanol which provide a prolongedduration of therapeutic effect (e.g., more than 6 or 8 hours, preferablymore than 12 hours, most preferably at least about 14 hours, 16 hours,18 hours, 20 hours or 24 hours) when given orally.

Another aspect of the invention provides for resistance of the oraldosage form of the invention to alcohol induced dose dumping. Thisproblem has been documented with several extended release opioidanalgesics and can have serious adverse consequences. (Sloan and Babul,Expert Opinion on Drug Delivery 2006; 3:489-97). There is therefore aneed for extended release opioids which do not evidence dose dumping inrelation to alcohol intake, which do not evidence clinically significantchanges in rate or extent of absorption in relation to alcohol intake,which do not evidence clinically significant pharmacodynamic variabilityin relation to alcohol intake, and which do not evidencebio-inequivalence of the dosage form when given with or without alcohol.

Many commercialized extended release opioids have been shown to have asignificant food effect. Another aspect of the invention provides forreduced fed fasted pharmacokinetic variability. An important issue withoral extended release products is its potential for “dose dumping” inrelation to food, where the active drug, intended for slow release, isinstead released rapidly, resulting in toxicity on the one hand and adecreased duration of effect on the other.

There is therefore a need for extended release opioids which do notevidence dose dumping in relation to food intake, which do not evidenceclinically significant changes in rate or extent of absorption inrelation to food intake, which do not evidence clinically significantpharmacodynamic variability in relation to food intake, and which do notevidence bio-inequivalence of the dosage form when given in a fed orfasted state.

A pharmaceutically acceptable dosage form of oral butorphanol for thetreatment of butorphanol responsive conditions beyond its short durationof action at a controlled rate over an extended period of time appearsto be lacking in the pharmaceutical and medical arts.

In view of the foregoing presentation, it is immediately apparent that aserious need exists for an improvement in the delivery of oralbutorphanol for its therapeutic effect. The need exists to provide anovel therapeutic composition comprising oral butorphanol, the needexists to provide a novel dosage form comprising oral butorphanol, andthe need to provide a novel method of administering butorphanol to apatient in need of butorphanol therapy. The invention provides an oral,relatively easy mode and manner of butorphanol administration incomparison with intranasal and parenteral administration.

To the applicants knowledge, no examples or working prototypeformulations of any modified release oral butorphanol have beendescribed in the prior art. Butorphanol is a challenging drug to developorally due to its high intrinsic clearance and the potential forsubstantial pharmacokinetic variability.

To the applicant's knowledge, there are no data heretofore demonstratingthe efficacy or safety of any oral pharmaceutical compositions ofmodified release butorphanol

To the applicant's knowledge, there is no prior art on the manufacture,use, efficacy, safety or abuse liability of any delayed onset, duodenaldelivery, jejunal delivery, ileal delivery, ileo-colonic delivery orcolonic delivery dosage forms of oral butorphanol for the treatment ofany butorphanol responsive medical conditions, including pain, cough,pruritus, and dyspnea.

There is a need for new pharmaceutical compositions and methods for thetreatment of butorphanol or opioid responsive medical conditions thathave high efficacy, good tolerability, are an alternative to theintranasal and parenteral routes, and provide consistentpharmacokinetics and pharmacodynamics.

DESCRIPTION OF THE INVENTION

The present invention is directed at modified release pharmaceuticalcompositions of oral butorphanol and methods for the treatment ofpatients with pain, dyspnea, cough, pruritus, urinary incontinence, andany other buprenorphine responsive medical condition.

The present invention is directed at modified release pharmaceuticalcompositions of oral butorphanol and methods for the treatment ofpatients with sickle cell disease, fibromylagia, acute herpes zoster,diarrhea, irritable bowel syndrome, visceral pain, neuropathic pain,restless leg syndrome, opioid addiction disorders and opioid dependence.

The present invention is directed at modified release pharmaceuticalcompositions of oral butorphanol and methods for the treatment forpatients in need of butorphanol.

The present invention is directed at modified release pharmaceuticalcompositions of oral butorphanol and methods for the treatment ofbutorphanol or opioid responsive medical conditions in a population ofpatients comprising at least some patients who are non-compliant withregular, scheduled or around the clock therapy with analgesics,particularly extended release analgesics.

The present invention is directed at modified release pharmaceuticalcompositions of oral butorphanol and methods for the treatment ofbutorphanol or opioid responsive medical conditions in a population ofsubjects comprising at least some subjects who take their opioidanalgesic for its euphoric, pleasureable or other non-medical effects.

The present invention is directed at modified release pharmaceuticalcompositions of oral butorphanol and methods for the treatment ofbutorphanol or opioid responsive medical conditions in a population ofsubjects comprising at least some subjects who can be expected to diverttheir supply of opioid analgesic into the illicit on non-medicaldistribution channels or who will misuse, abuse, share or sell theiropioid analgesic.

The present invention is directed at modified release pharmaceuticalcompositions of oral butorphanol and methods for the treatment ofbutorphanol or opioid responsive medical conditions in a population ofsubjects comprising at least some subjects who can be expected to taketheir dosage form concurrently or contemporaneously with alcohol,wherein the dosage form of the invention is resistant to alcoholassociated dose dumping.

The present invention is directed at modified release pharmaceuticalcompositions of oral butorphanol and methods for the treatment ofbutorphanol or opioid responsive medical conditions in a population ofsubjects comprising at least some subjects who can be expected to taketheir dosage form on as needed (PRN) basis, wherein the delayed onset,extended release dosage forms of butorphanol is less effective than whentaken on a scheduled (around the clock) basis.

The present invention is directed at modified release pharmaceuticalcompositions of oral butorphanol and methods for the treatment ofbutorphanol or opioid responsive medical conditions, where in the oraldosage form of the invention is resistant to dose dumping andpharmacokinetic variability in relation to the co-ingestion with orwithout food.

It is an object of certain embodiments of the present invention toprovide modified release formulations which give a substantiallyimproved dose range of dose proportional extent of absorption comparedto intranasal or oral immediate release dosage forms of butorphanol.

It is an object of certain embodiments of the present invention toprovide modified release formulations which give a substantially reducedpsychotomimetic effects compared to intranasal or oral immediate releasedosage forms of butorphanol.

It is an object of certain embodiments of the present invention toprovide modified release formulations which give a substantially reducedeuphoric, psychic, mood altering or pleasurable effect compared tointranasal oral immediate release dosage forms of butorphanol.

It is an object of certain embodiments of the present invention toprovide modified release formulations of butorphanol which: (i) areabuse resistant or abuse deterrent; (ii) are resistant to alcoholassociated dose dumping; (iii) are resistant to dose dumping andpharmacokinetic variability in relation to co-ingestion with or withoutfood; (iv) in delayed onset, extended release dosage forms provideimproved compliance with treatment; and/or (v) provide methods toachieve efficient dose titration and therapeutic effect with reducedside effects.

It is an object of certain embodiments of the present invention toprovide modified release formulations which give a substantiallyimproved safety for the treatment of chronic conditions (e.g., chronicpain) compared to intranasal or oral immediate release dosage forms ofbutorphanol.

It is an object of certain embodiments of the present invention toprovide bioavailable formulations for modified release dosage forms oforal butorphanol suitable for up to three times-a-day, twice-day or upto once-a-day administration to subjects in need of butorphanol.

It is an object of certain embodiments of the present invention toprovide bioavailable formulations for modified release dosage forms oforal butorphanol suitable for up to three times-a-day, twice-day or upto once-a-day administration which are a delayed onset and/or extendedduration of therapeutic effect.

It is an object of certain preferred embodiments of the presentinvention to provide oral formulations which provide therapeutic effectsfor up to about 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 or 30 hours.

In some preferred embodiments, the oral pharmaceutical compositions ofthe invention are modified release.

In some preferred embodiments, the modified release oral pharmaceuticalcompositions of the invention are delayed onset dosage forms ofbutorphanol.

In some preferred embodiments, the modified release oral pharmaceuticalcompositions of the invention are controlled release dosage forms ofbutorphanol.

In some preferred embodiments, the oral pharmaceutical compositions ofthe invention are modified release.

In some preferred embodiments, the oral pharmaceutical compositions ofthe invention are delayed onset, rapid release dosage forms ofbutorphanol.

In some preferred embodiments, the oral pharmaceutical compositions ofthe invention are delayed onset, extended release dosage forms ofbutorphanol.

In some preferred embodiments, the oral pharmaceutical compositions ofthe invention are delayed onset, pulsatile release dosage forms ofbutorphanol.

In some preferred embodiments, the oral pharmaceutical compositions ofthe invention are delayed duodenal release; or jejunal release; or ilealrelease; or ileo-colonic release; or colonic release.

In some embodiments, the modified release oral pharmaceuticalcompositions of the invention comprise some portion of the dose asimmediate release butorphanol.

In some embodiments, the present invention is directed at oralpharmaceutical composition for the treatment of butorphanol responsivemedical conditions comprising a therapeutically effective amount ofbutorphanol or a pharmaceutically acceptable salt of butorphanol, or amixture thereof.

In some embodiments, the present invention relates to oral butorphanolpharmaceutical compositions and methods for the treatment of pain,sickle cell disease, dyspnea, fibromylagia, acute herpes zoster,diarrhea, irritable bowel syndrome, visceral pain, neuropathic pain,pruritus (itch), urinary incontinence, acute or chronic cough, restlessleg syndrome, opioid addiction disorders and opioid dependence.

It is an object of certain preferred embodiments of the presentinvention to provide bioavailable oral butorphanol formulations suitablefor up to once-daily administration which improve the efficiency andquality of pain management.

It is an object of certain preferred embodiments of the presentinvention to substantially improve the efficiency and quality of painmanagement in human patients experiencing mild or moderate pain.

It is an object of some embodiments of the invention to provide modifiedrelease oral pharmaceutical compositions of butorphanol and methods forthe treatment of pain, addiction disorders and other butorphanolresponsive disorders, wherein the dosage form is administered at aprespecified dosing regimen. In some embodiments, said dosing regimen isassociated with reduced side effects, improved tolerability, improvedefficiency of therapeutic response, reduced breakthrough symptoms (e.g.,breakthrough pain) and reduced treatment discontinuation due to sideeffects.

It is an object of certain preferred embodiments of the presentinvention to treat patients who are believed to be at increased risk ofdrug abuse, opioid abuse, continued opioid abuse and relapse.

It is an object of certain preferred embodiments of the presentinvention to treat pain and addiction disorders in patients who have asuboptimal efficacy or safety response to intranasal butorphanol.

It is an object of certain preferred embodiments of the presentinvention to treat pain in patients who have a suboptimal efficacy orsafety response with other orally approved opioids (e.g., opioidsdescribed oral administration in the FDA's Orange Book. Goodman &Gilman's The Pharmacological Basis of Therapeutics (Brunton, Lazo andParker, eds, 11th ed., McGraw Hill (2005); Principles of Analgesic Usein the Treatment of Acute Pain and Cancer Pain, Fifth Ed., American,Pain Society (2003); Evidence Based Report of the U.S. Agency forHealthcare Research and Quality (AHRQ) on the Management of Cancer Pain,Report No. 35, AHRQ Publication No. 02-E002, October 2001; Carr et al. JNat Cancer Inst Monograph 2004; 32:23-31; Agency for Health Care Policyand Research Clinical Practice Guidelines for Cancer Pain Management,Guideline No. 9, AHCPR Publication No. 94-0592, March 1994; Agency forHealth Care Policy and Research Clinical Practice Guideline for AcutePain Management, Guideline No. 1, AHCPR Publication No. 92-0032,February, 1992; Guideline for the Management of Cancer Pain in Adults,American Pain Society, 2005; Guideline for the Management of Pain inOsteoarthritis, Rheumatoid Arthritis, and Juvenile Chronic Arthritis,2^(nd) Ed., American Pain Society, 2002), e.g., morphine, codeine,oxycodone, oxymorphone, hydromorphone, methadone, hydrocodone.

It is an object of certain preferred embodiments of the presentinvention to treat pain in patients who have a suboptimal efficacy orsafety response with other orally approved extended release opioids(e.g., MS Contin®, Kadian®, Avinza®, Ultram® ER, Opana® ER, Palladone®,Jurnista®).

It is an object of certain preferred embodiments of the presentinvention to substantially improve the efficiency and quality of painmanagement in human patients experiencing pain which is unresponsive orsuboptimally responsive to mu-receptor agonists.

It is an object of certain preferred embodiments of the presentinvention to substantially improve the efficiency and quality of painmanagement in human patients experiencing pain which is unresponsive orsuboptimally responsive to strong opioids.

It is an object of certain preferred embodiments of the presentinvention to substantially improve the efficiency and quality of painmanagement in human patients experiencing pain which is unresponsive orsuboptimally responsive to opioids classified as Schedule II (C-II) orSchedule III (C-III) opioids under the United States ControlledSubstance Act and regulations (as amended).

It is an object of some preferred embodiments to provide an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol which produces less drowsiness, nausea, dizziness,vomiting than after an equal amount (or dose) or lower amount (or dose)of intranasal butorphanol or immediate release oral butorphanol.

It is an object of some preferred embodiments to provide an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol which produces less abuse or abuse potential (e.g.,produces lower abuse scores for “drug effects”, “drug liking”,“coasting”, “take again”, as defined herein) than after an equal amount(or dose) or lower amount (or dose) of intranasal butorphanol orimmediate release oral butorphanol.

It is an object of some preferred embodiments to provide an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol which produces less neurologic, cognitive, motor andpsychomotor impairment (e.g., solution, suspension, tablet or capsule)given orally (e.g., produces lower impairment scores for “criticaltracking task”, “stop signal task” and “Tower of London” (TOL), asdefined herein) than after an equal amount (or dose) or lower amount (ordose) of intranasal butorphanol or immediate release oral butorphanol.

It is an object of certain preferred embodiments of the presentinvention to provide bioavailable oral butorphanol formulations whichprovide a substantially increased duration of effect as compared tointranasal butorphanol and oral immediate release butorphanolformulations.

It is an object of certain preferred embodiments of the invention toprovide an oral butorphanol formulation which are delayed onset,extended release dosage forms.

It is an object of certain preferred embodiments of the invention toprovide an oral butorphanol formulation which are delayed onset, rapidrelease dosage forms.

It is an object of certain preferred embodiments of the invention toprovide an oral butorphanol formulation which are delayed onset,pulsatile release dosage forms.

It is an object of certain preferred embodiments of the presentinvention to provide bioavailable formulations oral administration whichprovide a therapeutic effect for up to for up to about 8, 10, 12, or 16,18 or 24 hours after administration.

It is an object of certain preferred embodiments of the presentinvention to provide bioavailable formulations oral administrationsuitable for up to every 6, 8, 12, or 24 hour administration.

It is an object of certain preferred embodiments of the invention toprovide a method and formulations of oral butorphanol intended astherapeutic substitutes for unprescribed, illicit, or medicallyunsanctioned pharmaceutical grade or street grade opioids.

It is an object of certain preferred embodiments of the invention toprovide a method and formulations of oral butorphanol intended as partof an opioid substitution or opioid maintenance therapy in patients withan opioid addiction disorder or a polysubstance abuse disorder.

It is an object of certain preferred embodiments of the invention toprovide a method and formulations of oral butorphanol, said formulationshaving a reduced potential for drug abuse and drug diversion.

It is an object of certain preferred embodiments of the invention toprovide a method and formulations of oral butorphanol, said formulationshaving a reduced intrasubject or intersubject pharmacokineticvariability compared with intranasal butorphanol and immediate releaseoral butorphanol.

In some preferred embodiments, the invention comprises pharmaceuticalcomposition comprising a therapeutically effective amount of butorphanolor a pharmaceutically acceptable salt of butorphanol or a mixturethereof wherein the specifications of the invention applicable to thetreatment of pain are also applicable to the treatment of medicalconditions other than pain in subjects in need of butorphanol.

In some preferred embodiments, the invention provides oral butorphanolformulations which when evaluated versus other butorphanol dosage forms(e.g., intranasal butorphanol and immediate release oral butorphanol)provide a relative mean C_(max), AUC_(0-τ), and/or AUC_(0-inf) whose 90%confidence interval is outside the 80.00% to 125.00, under single-dosefasted test conditions in healthy subjects.

It is an object of certain preferred embodiments of the invention toprovide a method and formulations of oral butorphanol for the treatmentof pain in opioid tolerant patients (e.g., tolerant to morphine,oxymorphone, buprenorphine, oxycodone, hydromorphone, hydrocodone, etc).

It is an object of certain preferred embodiments of the invention toprovide a method and formulations of oral butorphanol for the treatmentof pain in patients with opioid hyperalgesia from the use of otheropioids.

The present invention also provides advantages in that equivalent, orhigher doses of butorphanol may be used with better efficacy and/orfewer side effects observed than with intranasal formulation or oralimmediate release formulations. For example, oral butorphanolformulations of the present invention may include the same amount or upto 5-fold higher daily maximum doses of intranasal butorphanol. However,even with these higher doses, formulations of the present inventionachieve better efficacy and fewer side effects.

Oral administration of butorphanol in modified release can producerobust, dose dependent therapeutic effects.

Surprisingly, oral administration of butorphanol delivered to the ileumor colon produces a robust therapeutic effect; said effect greater thatoral immediate release butorphanol delivered to the stomach.

In some preferred embodiments, the oral pharmaceutical compositions ofthe invention provide greater dose proportional bioavailability over a2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 15-fold dose range than the nasalformulations of butorphanol.

As used herein, “dose proportionality”, “dose-proportional” and “doseproportional bioavailability” means that change in dose by a particularpercentage changes the drug exposure by a similar percentage, asassessed by the area under the plasma concentration time curve andmaximum plasma concentration (C_(max)). For example, if a dosage formprovides dose proportional bioavailability, doubling the doseapproximately doubles the AUC and C_(max). Some drugs or dosage formsmay be dose proportional bioavailability over a narrow range of doses(e.g., 2 fold, or 3 fold), but may not be dose proportional over a widerrange of doses (e.g., 4, 5, 6, or 7 fold). Dose proportionality may beassessed by methods well known in the art. A particularly preferredmethod is described by Smith B P et al, Pharm Res 17:1278-1283, which ishereby incorporated in its entirety by reference.

In some embodiments, the invention provides an oral dosage form for thetreatment of butorphanol responsive conditions requiring chronicbutorphanol therapy which is designed to improve treatment complianceand deter episodic, occasional, intermittent, periodic, as needed, orPRN use of the dosage form by rendering the dosage form therapeuticallyineffective or suboptimally effective when taken episodically,intermittently, occasionally, periodically, on an as needed basis, orPRN, said dosage form comprising: (i) a therapeutically effective amountof butorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, and (ii) controlled release material to render said dosage formsuitable for modified release, said dosage form providing oralbutorphanol release distal to the stomach, duodenum, jejunum or ileum.

In some embodiments, the invention provides an oral dosage form for thetreatment of butorphanol responsive conditions requiring around theclock or time contingent butorphanol therapy which is designed toimprove treatment compliance and deter episodic, occasional,intermittent, periodic, as needed, or PRN use of the dosage form byrendering the dosage form therapeutically ineffective or suboptimallyeffective when taken episodically, intermittently, occasionally,periodically, on an as needed basis, or PRN, said dosage formcomprising: (i) a therapeutically effective amount of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, and (ii)controlled release material to render said dosage form suitable formodified release, said dosage form providing oral butorphanol releasedistal to the stomach, duodenum, jejunum or ileum.

In some embodiments, the invention provides an oral dosage form ofbutorphanol which is therapeutically effective but which deters theabuse and misuse of the dosage form by rendering the dosage devoid of orsubstantially devoid of euphoria, pleasurable effects, drug liking,psychic and mood alerting effects when taken episodically,intermittently, occasionally, periodically, on an as needed basis, orPRN, said dosage form comprising: (i) a therapeutically effective amountof butorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, and (ii) controlled release material to render said dosage formsuitable for modified release, said dosage form providing oralbutorphanol release distal to the stomach, duodenum, jejunum or ileum.

In some embodiments, the invention provides an oral dosage form ofbutorphanol which is therapeutically effective but which deters theabuse and misuse of the dosage form by delaying or substantiallydelaying euphoria, pleasurable effects, drug liking, psychic and moodalerting effects when taken regularly or when taken episodically,intermittently, occasionally, periodically, on an as needed basis, orPRN, said dosage form comprising: (i) a therapeutically effective amountof butorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, and (ii) controlled release material to render said dosage formsuitable for modified release, said dosage form providing oralbutorphanol release distal to the stomach, duodenum, jejunum or ileum.

Another aspect of the invention provides for improved compliance withtreatment. A major issue with pharmacologic management of chronicconditions is compliance with therapy. While extended release dosageforms assist this effort, compliance with extended releases dosage formsis still not adequate, which defeats the now widely accepted concept ofcontinuous suppression of pain. Many erroneously assume that medicationcompliance is not a problem in chronic pain (unlike, an asymptomaticcondition such as hypertension), since the patient will be reminded whento take their medication by the recurrence of pain. We have previouslydemonstrated that patients given unlimited access to PRN or as neededopioids consume lower doses of opioids but have worse analgesic outcomesthan patients who are placed on schedule around the clock therapy(Arkinstall et al, Pain, 2005; 62:169-78). The present inventionprovides a novel method to improve compliance by making the dosage formsubstantially ineffective when taken on a PRN basis but effective whentaken regularly.

In some embodiments, the invention provides a method of improvingtreatment compliance and deterring episodic, occasional, intermittent,periodic, as needed, or PRN use of the dosage form in subjects requiringaround the clock, scheduled or time contingent oral butorphanol therapyby rendering the dosage form therapeutically ineffective or suboptimallyeffective when taken episodically, intermittently, occasionally,periodically, on an as needed basis, or PRN, said dosage formtherapeutically effective in a substantial number of subjects when takenaround the clock, on scheduled basis or on time contingent basis,comprising: (i) a therapeutically effective amount of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, and (ii)controlled release material to render said dosage form suitable formodified release, said dosage form providing oral butorphanol releasedistal to the stomach, duodenum, jejunum or ileum.

In some embodiments, the invention provides a method of improvingtreatment compliance and deterring episodic, occasional, intermittent,periodic, as needed, or PRN use of the dosage form in subjects requiringchronic or prolonged oral butorphanol therapy by rendering the dosageform therapeutically ineffective or suboptimally effective when takenepisodically, intermittently, occasionally, periodically, on an asneeded basis, or PRN, said dosage form therapeutically effective in asubstantial number of subjects when taken around the clock, on scheduledbasis or on time contingent basis, comprising: (i) a therapeuticallyeffective amount of butorphanol, a pharmaceutically acceptable saltthereof, or a mixture thereof, and (ii) controlled release material torender said dosage form suitable for modified release, said dosage formproviding oral butorphanol release distal to the stomach, duodenum,jejunum or ileum.

In some embodiments, the invention provides a method of deterring abuseand misuse of oral butorphanol by rendering the dosage form devoid of orsubstantially devoid of euphoria, pleasurable effects, drug liking,psychic and mood alerting effects when taken episodically,intermittently, occasionally, periodically, on an as needed basis, orPRN, said dosage form comprising: (i) a therapeutically effective amountof butorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, and (ii) controlled release material to render said dosage formsuitable for modified release, said dosage form providing oralbutorphanol release distal to the stomach, duodenum, jejunum or ileum.

In some embodiments, the invention provides a method of deterring abuseand misuse of oral butorphanol by delaying or substantially delaying orreducing euphoria, pleasurable effects, drug liking, psychic and moodalerting effects when taken regularly or when taken episodically,intermittently, occasionally, periodically, on an as needed basis, orPRN, said dosage form comprising: (i) a therapeutically effective amountof butorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, and (ii) controlled release material to render said dosage formsuitable for modified release, said dosage form providing oralbutorphanol release distal to the stomach, duodenum, jejunum or ileum.

As used herein, when referring to use or administration of the oralbutorphanol dosage form of the invention in some embodiments to provideor confer improved treatment compliance and deterrence to episodic,occasional, intermittent, periodic, as needed, or PRN use of the dosageform, the term “episodic”, “occasional”, “intermittent”, “periodic”, “asneeded”, “PRN” and “PRN basis” refer to use or administration which isnon-consecutive, i.e., one oral butorphanol dose, given at its usualdosing interval (i) is not followed by a second administration or use atthe end of the usual dosing interval doses; or (ii) is separated fromthe second administration by at least one dose interval of non-use ornon-administration of the dosage form.

As used herein, when referring to use or administration of the oralbutorphanol dosage form of the invention in some embodiments to deterthe abuse and misuse of the dosage form by rendering the dosage devoidof or substantially devoid of euphoria, pleasurable effects, drugliking, psychic and mood alerting effects, the term “episodic”,“occasional”, “intermittent”, “periodic”, “as needed”, “PRN” and “PRNbasis” refer to use or administration which is non-consecutive, i.e.,one oral butorphanol dose, given at its usual dosing interval (i) is notfollowed by a second administration or use at the end of the usualdosing interval doses; or (ii) is separated from the secondadministration by at least one dose interval of non-use ornon-administration of the dosage form.

As used herein, when referring to use or administration of the oralbutorphanol dosage form of the invention in some embodiments to deterthe abuse and misuse of the dosage form by rendering the dosage devoidof or substantially devoid of euphoria, pleasurable effects, drugliking, psychic and mood alerting effects, the term “devoid of” or“substantially devoid of” means at least about 15%, or 20%, or 25%, or30%, or 35%, or 40%, or 50%, or 60%, or 70%, or 80% less euphoria,pleasurable effects, drug liking, psychic and mood alerting effectscompared with (i) an oral immediate release dosage form of butorphanol;or (ii) an oral controlled release dosage form which provides onset orsubstantial onset of release proximal to the duodenum, jejunum or ileum;or (iii) an intranasal dosage form of butorphanol.

In some embodiments, the invention provides an oral dosage formcomprising: (i) a therapeutically effective amount of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, and (ii)controlled release material to render said dosage form suitable formodified release, said dosage form providing butorphanol release distalto the stomach, duodenum, jejunum or ileum, said dosage form providingless side effects than intranasal butorphanol or oral immediate releasebutorphanol, said side effects measured after single dose administrationto opioid naïve subjects.

In some embodiments, the invention provides a method for reducing sideeffects, comprising administering an oral dosage form comprising: (i) atherapeutically effective amount of butorphanol, a pharmaceuticallyacceptable salt thereof, or a mixture thereof, and (ii) controlledrelease material to render said dosage form suitable for modifiedrelease, said dosage form providing butorphanol release distal to thestomach, duodenum, jejunum or ileum, said dosage form providing lessside effects than intranasal butorphanol or oral immediate releasebutorphanol, said side effects measured after single dose administrationto opioid naïve subjects.

In some embodiments, the present invention is directed to modifiedrelease oral pharmaceutical compositions of butorphanol which provideone or more of the following, when compared with intranasal butorphanol:(i) efficacy or improved efficacy; (ii) improved safety; (iii) improvedefficiency of the dosage form; (iv) improved dose proportional extent ofabsorption; (v) reduced variability in absorption; and (vi) reducedpotential for misuse, abuse, addiction and drug diversion. Without beingbound by theory, in some embodiments, the pharmaceutical compositionsand methods of the invention achieve their objectives at least in partthrough delivery of some, most, substantially all or all of the druginto the lower segments of the gastrointestinal tract (e.g., duodenalrelease; or jejunal release; or ileal release; or ileo-colonic release;or colonic release, or delayed onset, extended release).

In some embodiments, the modified release oral pharmaceuticalcompositions of butorphanol of the present invention improve theclinical efficacy, safety, tolerability, abuse resistance, doseproportional extent of absorption, predictability of clinical response,reproducibility of clinical response, therapeutic efficiency, and/orpharmacokinetics, said effect achieved through targeted gastrointestinaldelivery, availability, release, disintegration, dissolution, metabolismand/or absorption, said targeted delivery achieved at least in partthrough delivery of some, most, substantially all or all of the drug inlower segments of the gastrointestinal tract (e.g., duodenal release; orjejunal release; or ileal release; or ileo-colonic release; or colonicrelease, or delayed onset, extended release) said targetedgastrointestinal delivery achieved in some embodiments by incorporationof materials into the dosage form to provide time-controlled,diffusion-controlled pH-controlled, pressure-controlled, osmoticpressure controlled, microbially controlled and/or enzyme controlleddelivery or release.

In some embodiments, the oral controlled release; or delayed onset,rapid release; or delayed onset, extended release; or delayed onset,pulsatile release; or duodenal release pharmaceutical compositions ofbutorphanol result in one or more or all of the following benefits orcharacteristics when given at equal doses compared with immediaterelease oral dosage forms of butorphanol: increased dose proportionalextent of absorption; increased time to peak concentration (t_(max));reduced variability in extent of absorption (% coefficient of variationfor AUC_(0-inf) or AUC_(0-t)); reduced apparent oral clearance; lowerhydroxybutorphanol to butorphanol AUC_(0-inf) ratio; improved clinicalefficacy; improved safety; reduced side effects 0.5, 1, 2, 3, 4 5, 6, 7and/or 8 hours after oral ingestion of the dose; reduced abuse potentialin drug abusers and recreational drug users; reduced abuse potential insubjects using the drug in accordance with the instructions of themedical practitioner, manufacturer, approved prescribing information orpackage insert; reduced risk of drug diversion, addiction or iatrogenicaddiction; more predictable or reproducible clinical response; moreefficient clinical response; more predictable or reproducible analgesic;and more efficient analgesic response.

In some embodiments, the modified release pharmaceutical compositions ofbutorphanol liberate or deliver some, a lot, most, substantially all orall of the butorphanol in the dosage form upon reaching the duodenum,jejunum, terminal ileum, ileo-cecal junction, ascending colon,transverse colon or descending colon.

An important drawback with the use of opioids is the risk of drugaddiction, drug diversion and drug abuse. Although the use of opioidsfor non-medical purposes has existed throughout recorded human history,their abuse has increased significantly in the past few decades.

Pharmaceutical dosage forms containing butorphanol have been abused in avariety of settings, including patients with an addiction disorder whoobtain it from illicit sources, patients with pain who have apre-existing addiction disorder, patients with pain who have developedan addiction disorder following initiation of butorphanol or opioidtherapy and recreational drug users.

Another aspect of the invention provides for extended release dosageforms of butorphanol which resist abuse by patients, recreational drugusers and individuals with an addition disorder. Extended releaseopioids which do not require the incorporation of aversive andpotentially unsafe excipients into the formulation, which do not requirethe incorporation of sequestered or unsequestered opioid antagonists,which involve multiple mechanism of abuse deterrence and/or complementother safe and effective methods of abuse deterrence provide asignificant therapeutic advantage. The abuse deterrent pharmaceuticaldosage forms of the invention are achieved in part through delayedonset, extended release dosage forms which provide duodenal release,jejunal release, ileal release, ileo-colonic release or colonic releaseof the extended release butorphanol from the dosage form.

Preferably, the dosage forms of the invention release drug distal to thestomach, more preferably, distal to the duodenum, and most preferablydistal to the jejunum or ileum.

An important drawback with the use of opioid analgesics is the risk ofaddiction, diversion and abuse. Tampering extended release opioidformulations can deliver a significant dose in immediate release formand produce a variety of potentially serious or life threatening sideeffects. The focus of virtually all abuse resistant technology forextended release opioid formulations has been predicated on abusethrough tampering of the extended release dosage form by therecreational drug user or drug addicts. Such technologies purport to (i)frustrate attempts at dosage form tampering to extract the drug; (ii)nullify the effects of the drug if tampered, and/or (iii) produce anunpleasant or unwanted effect when consumed in tampered form.

In the applicants view, the foregoing technologies are not an adequatesolution to the problem of opioid abuse and fail to take into accountthe full spectrum of misuse, overuse and abuse of opioids. Suchtechnologies show an over-reliance on the experience of addictiondisorder clinics and emergency rooms which treat a very small minorityof non-medical opioid users, primarily “hard core” abusers who consumethe dosage form after tampering to maximize the delivered dose. Incontrast to this skewed observation derived from a minority ofnon-medical “hard core” opioid abusers, in a vast majority of cases, theabuse of opioid analgesics is with the intact dosage form (i.e., thedosage form has not been physically manipulated or tampered with toalter its absorption profile) and the opioid is taken by the usual(oral) route of administration. For example, a vast majority ofrecreational drug users and patients with an addiction disorder,including iatrogenic addiction disorders will seldom or never use anopioid intended to be taken orally by any other route (e.g.,intravenously after extraction and filtration, or by inhalation), norwill they physically manipulate or tamper the dosage form prior to oralingestion. This population has a different self-image of theirnon-medical opioid use and attempts to distinguish or differentiatethemselves and their use (abuse) from what they sometimes perceive as“reckless” and “irresponsible” use by “junkies”, “addicts”, “hard coreaddicts” or “real addicts”. In addition, a considerable amount of abuseof opioids is the intact ingestion at a dose which is simply higher thatthe medically prescribed dose. A majority of technologies described inthe art do not deal with the abuse of intact dosage forms of opioids.

In many cases, opioid abuse by the oral route involves immediate releaseor controlled release opioids. Such immediate release opioids generallyan onset of euphoric or psychic within about 15 to about 180 minutes orwithin about 15 to about 120 minutes or within about 15 to about 90minutes.

In some embodiments, the dosage forms of the invention reduces theintensity, frequency, duration, peak and/or total euphoric or psychiceffects when compared with oral, immediate release and oral, controlledrelease dosage forms containing the same drug. Consequently, in someembodiments, the dosage form of the invention will have a lowerpropensity for abuse and misuse.

In some embodiments, the butorphanol dosage forms of the invention havea reduced potential for abuse and misuse, including: (a) drug abuse inindividuals with a history of drug abuse or recreational drug use; (b)drug abuse in individuals with no prior history of drug abuse orrecreational drug use; (c) iatrogenic addiction, euphoria, orpleasurable effects in individuals who take the dosage form inaccordance with the approved prescribing information; (d) drugdiversion; (e) pharmaceutical company liability; (f) pharmacy break-ins,prescription forgeries, doctor shopping; (g) illicit (street)availability and price; and/or (g) mood altering effects, said reducedpotential abuse and misuse resulting in some embodiments at least inpart dosage forms that release all or substantially all of the activedrug distal to the duodenum, jejunum or ileum.

In some embodiments, the present invention is directed to oral dosageforms of butorphanol for the treatment of butorphanol responsiveconditions requiring chronic butorphanol therapy where the dosage formis designed to improve treatment compliance and deter episodic,occasional, intermittent, periodic, as needed, or PRN use, for exampleand without being bound by theory, by rendering the dosage formtherapeutically ineffective or suboptimally effective when takenepisodically, intermittently, occasionally, periodically, on an asneeded basis, or PRN, said dosage form comprising: (i) a therapeuticallyeffective amount of butorphanol, a pharmaceutically acceptable saltthereof, or a mixture thereof, and (ii) controlled release material torender said dosage form suitable for modified release, said dosage formproviding butorphanol release distal to the duodenum, jejunum or ileum.In some embodiments, said dosage form improves compliance or detersepisodic, occasional, intermittent, periodic, as needed, or PRN use bymore than about 1%, or 2%, or 3%, or 5%, or 7%, or 10%, or 12%, or 15%,or 18%, or 20%, or 25%, or 30%, or 35%, or 40%, or 50%, or 60%, or 70%,or 100%.

In some embodiments, the present invention is directed to oral dosageforms of butorphanol for the treatment of butorphanol responsiveconditions around the clock or time contingent butorphanol therapy wherethe dosage form is designed to improve treatment compliance and deterepisodic, occasional, intermittent, periodic, as needed, or PRN use, forexample and without being bound by theory, by rendering the dosage formtherapeutically ineffective or suboptimally effective when takenepisodically, intermittently, occasionally, periodically, on an asneeded basis, or PRN, said dosage form comprising: (i) a therapeuticallyeffective amount of butorphanol, a pharmaceutically acceptable saltthereof, or a mixture thereof, and (ii) controlled release material torender said dosage form suitable for modified release, said dosage formproviding butorphanol release distal to the duodenum, jejunum or ileum.In some embodiments, said dosage form improves compliance or detersepisodic, occasional, intermittent, periodic, as needed, or PRN use bymore than about 1%, or 2%, or 3%, or 5%, or 7%, or 10%, or 12%, or 15%,or 18%, or 20%, or 25%, or 30%, or 35%, or 40%, or 50%, or 60%, or 70%,or 100%.

In some embodiments, the present invention is directed at oralbutorphanol dosage forms which are therapeutically effective but whichdeter the abuse and misuse of the dosage form by recreational drug usersof opioids and opioid addicts by rendering the dosage devoid of orsubstantially devoid of euphoria, pleasurable, drug liking or other moodalerting effects when taken episodically, intermittently, occasionally,periodically, on an as needed basis, or PRN, said dosage formcomprising: (i) a therapeutically effective amount of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, and (ii)controlled release material to render said dosage form suitable formodified release, said dosage form providing butorphanol release distalto the duodenum, jejunum or ileum. In some embodiments, said dosage formreduces euphoria, pleasurable, drug liking or other mood alertingeffects by more than about 1%, or 2%, or 3%, or 5%, or 7%, or 10%, or12%, or 15%, or 18%, or 20%, or 25%, or 30%, or 35%, or 40%, or 50%, or60%, or 70%, or 100%.

In some embodiments, the present invention is directed at oralbutorphanol dosage forms which are therapeutically effective but whichdeter the abuse and misuse of the dosage form by recreational drug usersof opioids and opioid addicts, for example and without being bound bytheory, by rendering the dosage devoid of or substantially devoid of theinstant gratification from euphoria, pleasurable, drug liking or othermood alerting effects sought by recreational drug users of opioids andopioid addicts, said dosage form comprising: (i) a therapeuticallyeffective amount of butorphanol, a pharmaceutically acceptable saltthereof, or a mixture thereof, and (ii) controlled release material torender said dosage form suitable for modified release, said dosage formproviding butorphanol release distal to the duodenum, jejunum or ileum.In some embodiments, said dosage form reduces the instant gratificationfrom euphoria, pleasurable, drug liking or other mood alerting effectsby more than about 1%, or 2%, or 3%, or 5%, or 7%, or 10%, or 12%, or15%, or 18%, or 20%, or 25%, or 30%, or 35%, or 40%, or 50%, or 60%, or70%, or 100%.

In some embodiments, the orally administered butorphanol dosage forms ofthe invention have a reduced potential for abuse and misuse, includingfrequency, duration or magnitude of euphoria, sedation, drug liking,fatigue, cognitive impairment, motor impairment and CNS impairment.

In some embodiments, the present invention is directed at oralbutorphanol dosage forms which are therapeutically effective but whichhave reduced nausea, vomiting/retching, sedation, cognitive impairmentand fatigue, said dosage form comprising: (i) a therapeuticallyeffective amount of butorphanol, a pharmaceutically acceptable saltthereof, or a mixture thereof, and (ii) controlled release material torender said dosage form suitable for modified release, said dosage formproviding butorphanol release distal to the duodenum, jejunum or ileum.In some embodiments, said dosage form reduces nausea, vomiting/retching,sedation, cognitive impairment and/or fatigue by more than about 1%, or2%, or 3%, or 5%, or 7%, or 10%, or 12%, or 15%, or 18%, or 20%, or 25%,or 30%, or 35%, or 40%, or 50%, or 60%, or 70%, or 100%. In some otherembodiments, said dosage form reduces nausea, vomiting/retching,sedation, cognitive impairment and/or fatigue by more than about 1%, or2%, or 3%, or 5%, or 7%, or 10%, or 12%, or 15%, or 18%, or 20%, or 25%,or 30%, or 35%, or 40%, or 50%, or 60%, or 70%, or 100%, when measuredat up to 1, 2, 3, 4, 5, or 6 hours after dosing.

In some embodiments, the orally administered butorphanol dosage forms ofthe invention have a reduced street value, or a reduced frequency,duration or magnitude of sedation, drug liking fatigue, cognitiveimpairment, motor impairment and CNS impairment when assessed 0.5, or 1,or 1.5, or 2, or 2.5 or 3, or 4, or 5 or 6, or 7 or 8 hours afteringestion of the initial dose, or a subsequent dose by recreational drugusers, drug addicts, or opioid naïve healthy subjects.

In some embodiments, the orally administered butorphanol dosage forms ofthe invention have a reduced street value, or a reduced frequency,duration or magnitude of nausea, vomiting, sedation, drug likingfatigue, cognitive impairment, motor impairment, CNS impairment andother side effects, when assessed 0.5, or 1, or 1.5, or 2, or 2.5 or 3,or 4, or 5 or 6, or 7 or 8 hours after ingestion of the initial dose, ora subsequent dose by recreational drug users, drug addicts, or opioidnaïve healthy subjects, when compared with the an oral immediate releasesolid or solution dosage form of butorphanol, or an intranasal dosageform, or extended release dosage form which is not duodenal release,jejunal release, ileal release or colonic release. In some embodiments,said oral immediate release solid or solution dosage form or saidintranasal dosage form of butorphanol is administered at about the samedose, or at ≦about 90%, or ≦about 80%, or ≦about 75%, at ≦about 70%, or≦about 60%, or ≦about 50%, or ≦about 45%, or ≦about 40%, or ≦about 35%,at ≦about 30%, or ≦about 25%, or ≦about 20%, or ≦about 15% of the doseof orally administered butorphanol of the invention.

In some embodiments, the present invention discloses that the dose rangerequired to control pain with oral butorphanol dosage forms of theinvention in about 90% of subjects is less than or substantially lessthan the 8-fold dose range required with morphine, thereby providingseveral potential benefits, including more efficient titration process(adjusting the subject's dosage to provide acceptable pain reliefwithout unacceptable side effects), more therapeutically and costefficient control of symptoms, faster control of symptoms, reduced costof goods, reduced need for dose titration, reduced need for additionalvisits to the clinician, reduced need for a wider range of dosagestrengths and reduced pharmacy inventory. In some embodiments, the doserange of modified release oral butorphanol dosage forms of the inventionis at least about 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 60%, 70% or 75% less than oral morphine.

In some embodiments, the present invention discloses that the dose rangerequired to control pain with oral butorphanol dosage forms of theinvention in about 90% of subjects is less than or substantially lessthan the 4-fold dose range required with oxycodone, thereby providingseveral potential benefits, including more efficient titration process(adjusting the subject's dosage to provide acceptable pain reliefwithout unacceptable side effects), more therapeutically and costefficient control of symptoms, faster control of symptoms, reduced costof goods, reduced need for dose titration, reduced need for additionalvisits to the clinician, reduced need for a wider range of dosagestrengths and reduced pharmacy inventory. In some embodiments, the doserange of modified release oral butorphanol dosage forms of the inventionis at least about 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%,45%, or 50% less than oral oxycodone.

In some preferred embodiments, the dose range of modified release oralbutorphanol required to control pain in about 90% of subjects with oralbutorphanol dosage forms of the invention is less than about 3 fold, 3.5fold or 4 fold, or not more than about 3 fold, 3.5 fold, 4 fold, 4.5fold, 5 fold, 5.5 fold or 6 fold.

In some preferred embodiments where the dosage form is a delayed onsetoral butorphanol which releases most, substantially all or all theactive drug after an initial delay, said delayed onset dosage form islimited to compositions that deliver or release drug distal to thejejunum (i.e., ileal release, ileo-colonic release or colonic release).

In some preferred embodiments, the daily dose range of modified releaseoral butorphanol required to control pain in about 90% of subjects is 5mg to 60 mg, or 10 mg to 60 mg, or 10 mg to 50 mg, or 10 mg to 40 mg, or10 mg to 30 mg.

It should be noted that while the oral butorphanol daily dose rangerequired to control pain in about 90% of subjects in some embodiments ofthe invention is less than or substantially less than the 8-fold doserange seen with morphine which is the prototype opioid agonist, somepatients will require doses that exceed or far exceed the dose rangerequired to control pain in a substantial majority of subjects (e.g., 5,10, 15 or 20 fold higher than the dose range required to control pain inabout 90% of subjects said dosage form providing controlled release ordelayed onset, extended release, or duodenal release, or jejunal releaseor ileal release or colonic release), due to a variety ofpharmacokinetic and pharmacodynamic factors known in the art.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 5 mg to about 60 mg ofbutorphanol, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over two consecutive dosing intervals (AUC₀₋₂₄) from about 1ng·hr/mL to about 160 ng·hr/mL, and a mean maximum plasma concentrationof butorphanol from the first of the two consecutive doses from about0.1 ng/mL to about 6 ng/mL after repeated oral administration aboutevery 12 hours to steady-state conditions, said dosage form providingcontrolled release or delayed onset, extended release or duodenalrelease, or jejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 5 mg to about 60 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean maximum plasma concentration ofbutorphanol from about 0.1 ng/mL to about 6 ng/mL from the first of thetwo consecutive doses from a mean of about 2 hours to about 7 hours, anda mean minimum plasma concentration of butorphanol of about 0.05 ng/mLto about 4.5 ng/mL, said minimum concentration measured from a mean ofabout 8 to about 15 hours after repeated oral administration about every12 hours to steady-state conditions, said dosage form providingcontrolled release or delayed onset, extended release, or duodenalrelease, or jejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 5 mg to about 60 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over two consecutive dosing intervals (AUC₀₋₂₄) from about 1ng·hr/mL to about 160 ng·hr/mL, and a mean maximum plasma concentrationof butorphanol from the first of the two consecutive doses from about0.1 ng/mL to about 6 ng/mL from a mean of about 2 hours to about 7 hoursafter repeated oral administration about every 12 hours to steady-stateconditions, said dosage form providing controlled release or delayedonset, extended release or duodenal release, or jejunal release or ilealrelease or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 5 mg to about 60 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over two consecutive dosing intervals (AUC₀₋₂₄) from about 1ng·hr/mL to about 160 ng·hr/mL, a mean maximum plasma concentration ofbutorphanol from the first of the two consecutive doses from about 0.1ng/mL to about 6 ng/mL from a mean of about 2 hours to about 7 hours,and a mean minimum plasma concentration of butorphanol of about 0.05ng/mL to about 4.5 ng/mL, said minimum concentration measured from amean of about 8 to about 15 hours after repeated oral administrationabout every 12 hours to steady-state conditions, said dosage formproviding controlled release or delayed onset, extended release, orduodenal release, or jejunal release or ileal release or colonicrelease.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 10 mg to about 120 mg ofbutorphanol, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over a single dosing interval (AUC₀₋₂₄) from about 1 ng·hr/mLto about 160 ng·hr/mL, and a mean maximum plasma concentration ofbutorphanol from about 0.1 ng/mL to about 6 ng/mL after repeated oraladministration about every 24 hours to steady-state conditions, saiddosage form providing controlled release or delayed onset, extendedrelease, or duodenal release, or jejunal release or ileal release orcolonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 10 mg to about 120 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean maximum plasma concentration ofbutorphanol from about 0.1 ng/mL to about 6 ng/mL from a mean of about 3hours to about 18 hours, and a mean minimum plasma concentration ofbutorphanol of about 0.05 ng/mL to about 4.5 ng/mL, said minimumconcentration measured from a mean of about 20 to about 28 hours afterrepeated oral administration about every 24 hours to steady-stateconditions, said dosage form providing controlled release or delayedonset, extended release, or duodenal release, or jejunal release orileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 10 mg to about 120 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over a single dosing interval (AUC₀₋₂₄) from about 1 ng·hr/mLto about 160 ng·hr/mL, and a mean maximum plasma concentration ofbutorphanol from about 0.1 ng/mL to about 6 ng/mL from a mean of about 3hours to about 18 hours after repeated oral administration about every24 hours to steady-state conditions, said dosage form providingcontrolled release or delayed onset, extended release, or duodenalrelease, or jejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 10 mg to about 120 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over a single dosing interval (AUC₀₋₂₄) from about 1 ng·hr/mLto about 160 ng·hr/mL, and a mean maximum plasma concentration ofbutorphanol from about 0.1 ng/mL to about 6 ng/mL from a mean of about 3hours to about 18 hours, and a mean minimum plasma concentration ofbutorphanol of about 0.05 ng/mL to about 4.5 ng/mL, said minimumconcentration measured from a mean of about 20 to about 28 hours afterrepeated oral administration every 24 hours to steady-state conditions,said dosage form providing controlled release or delayed onset, extendedrelease, or duodenal release, or jejunal release or ileal release orcolonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 10 mg to about 40 mg ofbutorphanol, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over two consecutive dosing intervals (AUC₀₋₂₄) from about 2ng·hr/mL to about 110 ng·hr/mL, and a mean maximum plasma concentrationof butorphanol from the first of the two consecutive doses from about0.2 ng/mL to about 4 ng/mL after repeated oral administration aboutevery 12 hours to steady-state conditions, said dosage form providingcontrolled release or delayed onset, extended release, or duodenalrelease, or jejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 10 mg to about 40 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean maximum plasma concentration ofbutorphanol from about 0.2 ng/mL to about 4 ng/mL from the first of thetwo consecutive doses from a mean of about 2 hours to about 7 hours, anda mean minimum plasma concentration of butorphanol of about 0.1 ng/mL toabout 3 ng/mL, said minimum concentration measured from a mean of about8 to about 15 hours after repeated oral administration about every 12hours to steady-state conditions, said dosage form providing controlledrelease or delayed onset, extended release, or duodenal release, orjejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 10 mg to about 40 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over two consecutive dosing intervals (AUC₀₋₂₄) from about 2ng·hr/mL to about 110 ng·hr/mL, and a mean maximum plasma concentrationof butorphanol from the first of the two consecutive doses from about0.2 ng/mL to about 4 ng/mL from a mean of about 2 hours to about 7 hoursafter repeated oral administration about every 12 hours to steady-stateconditions, said dosage form providing controlled release or delayedonset, extended release, or duodenal release, or jejunal release orileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 10 mg to about 40 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over two consecutive dosing intervals (AUC₀₋₂₄) from about 2ng·hr/mL to about 110 ng·hr/mL, a mean maximum plasma concentration ofbutorphanol from the first of the two consecutive doses from about 0.2ng/mL to about 4 ng/mL from a mean of about 2 hours to about 7 hours,and a mean minimum plasma concentration of butorphanol of about 0.1ng/mL to about 3 ng/mL, said minimum concentration measured from a meanof about 8 to about 15 hours after repeated oral administration aboutevery 12 hours to steady-state conditions, said dosage form providingcontrolled release or delayed onset, extended release, or duodenalrelease, or jejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 20 mg to about 80 mg ofbutorphanol, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over a single dosing interval (AUC₀₋₂₄) from about 2 ng·hr/mLto about 110 ng·hr/mL, and a mean maximum plasma concentration ofbutorphanol from about 0.2 ng/mL to about 4 ng/mL after repeated oraladministration about every 24 hours to steady-state conditions, saiddosage form providing controlled release or delayed onset, extendedrelease, or duodenal release, or jejunal release or ileal release orcolonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 20 mg to about 80 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean maximum plasma concentration ofbutorphanol from about 0.2 ng/mL to about 4 ng/mL from a mean of about 3hours to about 18 hours, and a mean minimum plasma concentration ofbutorphanol of about 0.1 ng/mL to about 3 ng/mL, said minimumconcentration measured from a mean of about 20 to about 28 hours afterrepeated oral administration about every 24 hours to steady-stateconditions, said dosage form providing controlled release or delayedonset, extended release, or duodenal release, or jejunal release orileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 20 mg to about 80 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over a single dosing interval (AUC₀₋₂₄) from about 2 ng·hr/mLto about 110 ng·hr/mL, and a mean maximum plasma concentration ofbutorphanol from about 0.2 ng/mL to about 4 ng/mL from a mean of about 3hours to about 18 hours after repeated oral administration about every24 hours to steady-state conditions, said dosage form providingcontrolled release or delayed onset, extended release, or duodenalrelease, or jejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 20 mg to about 80 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over a single dosing interval (AUC₀₋₂₄) from about 2 ng·hr/mLto about 110 ng·hr/mL, and a mean maximum plasma concentration ofbutorphanol from about 0.2 ng/mL to about 4 ng/mL from a mean of about 3hours to about 18 hours, and a mean minimum plasma concentration ofbutorphanol of about 0.1 ng/mL to about 3 ng/mL, said minimumconcentration measured from a mean of about 20 to about 28 hours afterrepeated oral administration every 24 hours to steady-state conditions,said dosage form providing controlled release or delayed onset, extendedrelease, or duodenal release, or jejunal release or ileal release orcolonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 5 mg to about 80 mg ofbutorphanol, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over two consecutive dosing intervals (AUC₀₋₂₄) from about 1ng·hr/mL to about 220 ng·hr/mL, and a mean maximum plasma concentrationof butorphanol from the first of the two consecutive doses from about0.1 ng/mL to about 8 ng/mL after repeated oral administration aboutevery 12 hours to steady-state conditions, said dosage form providingcontrolled release or delayed onset, extended release, or duodenalrelease, or jejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 5 mg to about 80 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean maximum plasma concentration ofbutorphanol from about 0.1 ng/mL to about 8 ng/mL from the first of thetwo consecutive doses from a mean of about 2 hours to about 7 hours, anda mean minimum plasma concentration of butorphanol of about 0.05 ng/mLto about 6 ng/mL, said minimum concentration measured from a mean ofabout 8 to about 15 hours after repeated oral administration about every12 hours to steady-state conditions, said dosage form providingcontrolled release or delayed onset, extended release, or duodenalrelease, or jejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 5 mg to about 80 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over two consecutive dosing intervals (AUC₀₋₂₄) from about 1ng·hr/mL to about 220 ng·hr/mL, and a mean maximum plasma concentrationof butorphanol from the first of the two consecutive doses from about0.1 ng/mL to about 8 ng/mL from a mean of about 2 hours to about 7 hoursafter repeated oral administration about every 12 hours to steady-stateconditions, said dosage form providing controlled release or delayedonset, extended release, or duodenal release, or jejunal release orileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 5 mg to about 80 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over two consecutive dosing intervals (AUC₀₋₂₄) from about 1ng·hr/mL to about 220 ng·hr/mL, a mean maximum plasma concentration ofbutorphanol from the first of the two consecutive doses from about 0.1ng/mL to about 8 ng/mL from a mean of about 2 hours to about 7 hours,and a mean minimum plasma concentration of butorphanol of about 0.05ng/mL to about 6 ng/mL, said minimum concentration measured from a meanof about 8 to about 15 hours after repeated oral administration aboutevery 12 hours to steady-state conditions, said dosage form providingcontrolled release or delayed onset, extended release, or duodenalrelease, or jejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 10 mg to about 120 mg ofbutorphanol, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over a single dosing interval (AUC₀₋₂₄) from about 1 ng·hr/mLto about 220 ng·hr/mL, and a mean maximum plasma concentration ofbutorphanol from about 0.1 ng/mL to about 8 ng/mL after repeated oraladministration about every 24 hours to steady-state conditions, saiddosage form providing controlled release or delayed onset, extendedrelease, or duodenal release, or jejunal release or ileal release orcolonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 10 mg to about 120 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean maximum plasma concentration ofbutorphanol from about 0.1 ng/mL to about 8 ng/mL from a mean of about 3hours to about 18 hours, and a mean minimum plasma concentration ofbutorphanol of about 0.05 ng/mL to about 6 ng/mL, said minimumconcentration measured from a mean of about 20 to about 28 hours afterrepeated oral administration about every 24 hours to steady-stateconditions, said dosage form providing controlled release or delayedonset, extended release, or duodenal release, or jejunal release orileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 10 mg to about 120 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over a single dosing interval (AUC₀₋₂₄) from about 1 ng·hr/mLto about 220 ng·hr/mL, and a mean maximum plasma concentration ofbutorphanol from about 0.1 ng/mL to about 8 ng/mL from a mean of about 3hours to about 18 hours after repeated oral administration about every24 hours to steady-state conditions, said dosage form providingcontrolled release or delayed onset, extended release, or duodenalrelease, or jejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the range in daily dosages required to control pain insubstantially all human patients, comprising administering a modifiedrelease oral butorphanol comprising from about 10 mg to about 120 mg ofbutorphanol, a pharmaceutically acceptable salt thereof, or a mixturethereof, which provides a mean a systemic exposure of butorphanol asassessed by the mean butorphanol area under the plasma concentrationtime curve over a single dosing interval (AUC₀₋₂₄) from about 1 ng·hr/mLto about 220 ng·hr/mL, and a mean maximum plasma concentration ofbutorphanol from about 0.1 ng/mL to about 8 ng/mL from a mean of about 3hours to about 18 hours, and a mean minimum plasma concentration ofbutorphanol of about 0.05 ng/mL to about 6 ng/mL, said minimumconcentration measured from a mean of about 20 to about 28 hours afterrepeated oral administration every 24 hours to steady-state conditions,said dosage form providing controlled release or delayed onset, extendedrelease, or duodenal release, or jejunal release or ileal release orcolonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 5 mg to about 60 mg of butorphanol,which provides a mean a systemic exposure of butorphanol as assessed bythe mean butorphanol area under the plasma concentration time curve overtwo consecutive dosing intervals (AUC₀₋₂₄) from about 1 ng·hr/mL toabout 160 ng·hr/mL, and a mean maximum plasma concentration ofbutorphanol from the first of the two consecutive doses from about 0.1ng/mL to about 6 ng/mL after repeated oral administration about every 12hours to steady-state conditions, said dosage form providing controlledrelease or delayed onset, extended release, or duodenal release, orjejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 5 mg to about 60 mg of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean maximum plasma concentration of butorphanol from about0.1 ng/mL to about 6 ng/mL from the first of the two consecutive dosesfrom a mean of about 2 hours to about 7 hours, and a mean minimum plasmaconcentration of butorphanol of about 0.05 ng/mL to about 4.5 ng/mL,said minimum concentration measured from a mean of about 8 to about 15hours after repeated oral administration about every 12 hours tosteady-state conditions, said dosage form providing controlled releaseor delayed onset, extended release, or duodenal release, or jejunalrelease or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 5 mg to about 60 mg of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean a systemic exposure of butorphanol as assessed by themean butorphanol area under the plasma concentration time curve over twoconsecutive dosing intervals (AUC₀₋₂₄) from about 1 ng·hr/mL to about160 ng·hr/mL, and a mean maximum plasma concentration of butorphanolfrom the first of the two consecutive doses from about 0.1 ng/mL toabout 6 ng/mL from a mean of about 2 hours to about 7 hours afterrepeated oral administration about every 12 hours to steady-stateconditions, said dosage form providing controlled release or delayedonset, extended release, or duodenal release, or jejunal release orileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 5 mg to about 60 mg of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean a systemic exposure of butorphanol as assessed by themean butorphanol area under the plasma concentration time curve over twoconsecutive dosing intervals (AUC₀₋₂₄) from about 1 ng·hr/mL to about160 ng·hr/mL, a mean maximum plasma concentration of butorphanol fromthe first of the two consecutive doses from about 0.1 ng/mL to about 6ng/mL from a mean of about 2 hours to about 7 hours, and a mean minimumplasma concentration of butorphanol of about 0.05 ng/mL to about 4.5ng/mL, said minimum concentration measured from a mean of about 8 toabout 15 hours after repeated oral administration about every 12 hoursto steady-state conditions, said dosage form providing controlledrelease or delayed onset, extended release, or duodenal release, orjejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 10 mg to about 120 mg of butorphanol,which provides a mean a systemic exposure of butorphanol as assessed bythe mean butorphanol area under the plasma concentration time curve overa single dosing interval (AUC₀₋₂₄) from about 1 ng·hr/mL to about 160ng·hr/mL, and a mean maximum plasma concentration of butorphanol fromabout 0.1 ng/mL to about 6 ng/mL after repeated oral administrationabout every 24 hours to steady-state conditions, said dosage formproviding controlled release or delayed onset, extended release, orduodenal release, or jejunal release or ileal release or colonicrelease.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 10 mg to about 120 mg of butorphanol,a pharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean maximum plasma concentration of butorphanol from about0.1 ng/mL to about 6 ng/mL from a mean of about 3 hours to about 18hours, and a mean minimum plasma concentration of butorphanol of about0.05 ng/mL to about 4.5 ng/mL, said minimum concentration measured froma mean of about 20 to about 28 hours after repeated oral administrationabout every 24 hours to steady-state conditions, said dosage formproviding controlled release or delayed onset, extended release, orduodenal release, or jejunal release or ileal release or colonicrelease.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 10 mg to about 120 mg of butorphanol,a pharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean a systemic exposure of butorphanol as assessed by themean butorphanol area under the plasma concentration time curve over asingle dosing interval (AUC₀₋₂₄) from about 1 ng·hr/mL to about 160ng·hr/mL, and a mean maximum plasma concentration of butorphanol fromabout 0.1 ng/mL to about 6 ng/mL from a mean of about 3 hours to about18 hours after repeated oral administration about every 24 hours tosteady-state conditions, said dosage form providing controlled releaseor delayed onset, extended release, or duodenal release, or jejunalrelease or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 10 mg to about 120 mg of butorphanol,a pharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean a systemic exposure of butorphanol as assessed by themean butorphanol area under the plasma concentration time curve over asingle dosing interval (AUC₀₋₂₄) from about 1 ng·hr/mL to about 160ng·hr/mL, and a mean maximum plasma concentration of butorphanol fromabout 0.1 ng/mL to about 6 ng/mL from a mean of about 3 hours to about18 hours, and a mean minimum plasma concentration of butorphanol ofabout 0.05 ng/mL to about 4.5 ng/mL, said minimum concentration measuredfrom a mean of about 20 to about 28 hours after repeated oraladministration every 24 hours to steady-state conditions, said dosageform providing controlled release or delayed onset, extended release, orduodenal release, or jejunal release or ileal release or colonicrelease.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 10 mg to about 40 mg of butorphanol,which provides a mean a systemic exposure of butorphanol as assessed bythe mean butorphanol area under the plasma concentration time curve overtwo consecutive dosing intervals (AUC₀₋₂₄) from about 2 ng·hr/mL toabout 110 ng·hr/mL, and a mean maximum plasma concentration ofbutorphanol from the first of the two consecutive doses from about 0.2ng/mL to about 4 ng/mL after repeated oral administration about every 12hours to steady-state conditions, said dosage form providing controlledrelease or delayed onset, extended release, or duodenal release, orjejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 10 mg to about 40 mg of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean maximum plasma concentration of butorphanol from about0.2 ng/mL to about 4 ng/mL from the first of the two consecutive dosesfrom a mean of about 2 hours to about 7 hours, and a mean minimum plasmaconcentration of butorphanol of about 0.1 ng/mL to about 3 ng/mL, saidminimum concentration measured from a mean of about 8 to about 15 hoursafter repeated oral administration about every 12 hours to steady-stateconditions, said dosage form providing controlled release or delayedonset, extended release, or duodenal release, or jejunal release orileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 10 mg to about 40 mg of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean a systemic exposure of butorphanol as assessed by themean butorphanol area under the plasma concentration time curve over twoconsecutive dosing intervals (AUC₀₋₂₄) from about 2 ng·hr/mL to about110 ng·hr/mL, and a mean maximum plasma concentration of butorphanolfrom the first of the two consecutive doses from about 0.2 ng/mL toabout 4 ng/mL from a mean of about 2 hours to about 7 hours afterrepeated oral administration about every 12 hours to steady-stateconditions, said dosage form providing controlled release or delayedonset, extended release, or duodenal release, or jejunal release orileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 10 mg to about 40 mg of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean a systemic exposure of butorphanol as assessed by themean butorphanol area under the plasma concentration time curve over twoconsecutive dosing intervals (AUC₀₋₂₄) from about 2 ng·hr/mL to about110 ng·hr/mL, a mean maximum plasma concentration of butorphanol fromthe first of the two consecutive doses from about 0.2 ng/mL to about 4ng/mL from a mean of about 2 hours to about 7 hours, and a mean minimumplasma concentration of butorphanol of about 0.1 ng/mL to about 3 ng/mL,said minimum concentration measured from a mean of about 8 to about 15hours after repeated oral administration about every 12 hours tosteady-state conditions, said dosage form providing controlled releaseor delayed onset, extended release, or duodenal release, or jejunalrelease or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 20 mg to about 80 mg of butorphanol,which provides a mean a systemic exposure of butorphanol as assessed bythe mean butorphanol area under the plasma concentration time curve overa single dosing interval (AUC₀₋₂₄) from about 2 ng·hr/mL to about 110ng·hr/mL, and a mean maximum plasma concentration of butorphanol fromabout 0.2 ng/mL to about 4 ng/mL after repeated oral administrationabout every 24 hours to steady-state conditions, said dosage formproviding controlled release or delayed onset, extended release, orduodenal release, or jejunal release or ileal release or colonicrelease.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 20 mg to about 80 mg of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean maximum plasma concentration of butorphanol from about0.2 ng/mL to about 4 ng/mL from a mean of about 3 hours to about 18hours, and a mean minimum plasma concentration of butorphanol of about0.1 ng/mL to about 3 ng/mL, said minimum concentration measured from amean of about 20 to about 28 hours after repeated oral administrationabout every 24 hours to steady-state conditions, said dosage formproviding controlled release or delayed onset, extended release, orduodenal release, or jejunal release or ileal release or colonicrelease.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 20 mg to about 80 mg of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean a systemic exposure of butorphanol as assessed by themean butorphanol area under the plasma concentration time curve over asingle dosing interval (AUC₀₋₂₄) from about 2 ng·hr/mL to about 110ng·hr/mL, and a mean maximum plasma concentration of butorphanol fromabout 0.2 ng/mL to about 4 ng/mL from a mean of about 3 hours to about18 hours after repeated oral administration about every 24 hours tosteady-state conditions, said dosage form providing controlled releaseor delayed onset, extended release, or duodenal release, or jejunalrelease or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 20 mg to about 80 mg of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean a systemic exposure of butorphanol as assessed by themean butorphanol area under the plasma concentration time curve over asingle dosing interval (AUC₀₋₂₄) from about 2 ng·hr/mL to about 110ng·hr/mL, and a mean maximum plasma concentration of butorphanol fromabout 0.2 ng/mL to about 4 ng/mL from a mean of about 3 hours to about18 hours, and a mean minimum plasma concentration of butorphanol ofabout 0.1 ng/mL to about 3 ng/mL, said minimum concentration measuredfrom a mean of about 20 to about 28 hours after repeated oraladministration every 24 hours to steady-state conditions, said dosageform providing controlled release or delayed onset, extended release, orduodenal release, or jejunal release or ileal release or colonicrelease.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 5 mg to about 80 mg of butorphanol,which provides a mean a systemic exposure of butorphanol as assessed bythe mean butorphanol area under the plasma concentration time curve overtwo consecutive dosing intervals (AUC₀₋₂₄) from about 1 ng·hr/mL toabout 220 ng·hr/mL, and a mean maximum plasma concentration ofbutorphanol from the first of the two consecutive doses from about 0.1ng/mL to about 8 ng/mL after repeated oral administration about every 12hours to steady-state conditions, said dosage form providing controlledrelease or delayed onset, extended release, or duodenal release, orjejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 5 mg to about 80 mg of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean maximum plasma concentration of butorphanol from about0.1 ng/mL to about 8 ng/mL from the first of the two consecutive dosesfrom a mean of about 2 hours to about 7 hours, and a mean minimum plasmaconcentration of butorphanol of about 0.05 ng/mL to about 6 ng/mL, saidminimum concentration measured from a mean of about 8 to about 15 hoursafter repeated oral administration about every 12 hours to steady-stateconditions, said dosage form providing controlled release or delayedonset, extended release, or duodenal release, or jejunal release orileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 5 mg to about 80 mg of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean a systemic exposure of butorphanol as assessed by themean butorphanol area under the plasma concentration time curve over twoconsecutive dosing intervals (AUC₀₋₂₄) from about 1 ng·hr/mL to about220 ng·hr/mL, and a mean maximum plasma concentration of butorphanolfrom the first of the two consecutive doses from about 0.1 ng/mL toabout 8 ng/mL from a mean of about 2 hours to about 7 hours afterrepeated oral administration about every 12 hours to steady-stateconditions, said dosage form providing controlled release or delayedonset, extended release, or duodenal release, or jejunal release orileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 5 mg to about 80 mg of butorphanol, apharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean a systemic exposure of butorphanol as assessed by themean butorphanol area under the plasma concentration time curve over twoconsecutive dosing intervals (AUC₀₋₂₄) from about 1 ng·hr/mL to about220 ng·hr/mL, a mean maximum plasma concentration of butorphanol fromthe first of the two consecutive doses from about 0.1 ng/mL to about 8ng/mL from a mean of about 2 hours to about 7 hours, and a mean minimumplasma concentration of butorphanol of about 0.05 ng/mL to about 6ng/mL, said minimum concentration measured from a mean of about 8 toabout 15 hours after repeated oral administration about every 12 hoursto steady-state conditions, said dosage form providing controlledrelease or delayed onset, extended release, or duodenal release, orjejunal release or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 10 mg to about 120 mg of butorphanol,which provides a mean a systemic exposure of butorphanol as assessed bythe mean butorphanol area under the plasma concentration time curve overa single dosing interval (AUC₀₋₂₄) from about 1 ng·hr/mL to about 220ng·hr/mL, and a mean maximum plasma concentration of butorphanol fromabout 0.1 ng/mL to about 8 ng/mL after repeated oral administrationabout every 24 hours to steady-state conditions, said dosage formproviding controlled release or delayed onset, extended release, orduodenal release, or jejunal release or ileal release or colonicrelease.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 10 mg to about 120 mg of butorphanol,a pharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean maximum plasma concentration of butorphanol from about0.1 ng/mL to about 8 ng/mL from a mean of about 3 hours to about 18hours, and a mean minimum plasma concentration of butorphanol of about0.05 ng/mL to about 6 ng/mL, said minimum concentration measured from amean of about 20 to about 28 hours after repeated oral administrationabout every 24 hours to steady-state conditions, said dosage formproviding controlled release or delayed onset, extended release, orduodenal release, or jejunal release or ileal release or colonicrelease.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 10 mg to about 120 mg of butorphanol,a pharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean a systemic exposure of butorphanol as assessed by themean butorphanol area under the plasma concentration time curve over asingle dosing interval (AUC₀₋₂₄) from about 1 ng·hr/mL to about 220ng·hr/mL, and a mean maximum plasma concentration of butorphanol fromabout 0.1 ng/mL to about 8 ng/mL from a mean of about 3 hours to about18 hours after repeated oral administration about every 24 hours tosteady-state conditions, said dosage form providing controlled releaseor delayed onset, extended release, or duodenal release, or jejunalrelease or ileal release or colonic release.

In some preferred embodiments, the dosage form provides a method forreducing the number of dose adjustments or dose titrations required tocontrol pain over the first month of treatment in substantially allhuman patients, comprising administering a modified release oralbutorphanol comprising from about 10 mg to about 120 mg of butorphanol,a pharmaceutically acceptable salt thereof, or a mixture thereof, whichprovides a mean a systemic exposure of butorphanol as assessed by themean butorphanol area under the plasma concentration time curve over asingle dosing interval (AUC₀₋₂₄) from about 1 ng·hr/mL to about 220ng·hr/mL, and a mean maximum plasma concentration of butorphanol fromabout 0.1 ng/mL to about 8 ng/mL from a mean of about 3 hours to about18 hours, and a mean minimum plasma concentration of butorphanol ofabout 0.05 ng/mL to about 6 ng/mL, said minimum concentration measuredfrom a mean of about 20 to about 28 hours after repeated oraladministration every 24 hours to steady-state conditions, said dosageform providing controlled release or delayed onset, extended release, orduodenal release, or jejunal release or ileal release or colonicrelease.

A major challenge with the administration of more than one drugconcurrently or in close proximity to each other is the occurrence ofincreased adverse effects from the combined and simultaneous high plasmaconcentrations of more than one drug producing the same or similar sideeffects through additive, super-additive or synergistic effects. Forexample, butorphanol may be used in conjunction with other drugs for thetreatment of the same or different condition or side effect. Such otherdrugs can produce similar or the same side effects as butorphanol,including sedation, nausea, vomiting, and fatigue. Unfortunately, inmany cases, using an alternative concomitant drug is not a practicaloption. In some embodiments, the present invention provides oralpharmaceutical compositions and methods to reduce the frequency,duration or magnitude of side effects from such concurrent, allowing forthe advantageous use of drugs with similar or the same side effects asbutorphanol.

Butorphanol is widely believed to be inappropriate to give orally,resulting in the need to: (i) administer the opioid by the parenteralroute, with all of its sterility, cost, route accessibility to patients,and technical challenges; (ii) administer an intranasal dosage form withits limited duration of action, high incidence of side effects, limiteddosage range, limited dose range showing dose proportionalbioavailability, low patient acceptance and higher potential fortampering and abuse.

In some embodiments of the present invention the oral dosage fromdelivers most, substantially all or all of the butorphanol into thelower segments of the gastrointestinal tract (e.g., delayed onset, rapidrelease; or delayed onset, extended release; or delayed onset, pulsatilerelease; or duodenal release; or jejunal release; or ileal release; orileo-colonic release; or colonic release) and the dosage form is bestsuited under certain circumstances (e.g., when the dosage form is adelayed onset form) for the treatment of signs and symptoms which do notrequire a rapid onset of effect from “one of”, intermittent or episodicuse of the dosage form or which are not administered as a single dose,or an intermittent dose or for episodic use. For example, if anindividual has a new onset muscle tension headache or a new onsetmigraine, in some embodiments of the invention where the dosage form ofthe present invention delivers most, substantially all or all of thebutorphanol into the lower segments of the gastrointestinal tract, itwould usually be impractical to use the dosage form to produce ameaningful pharmacologic response due to the unacceptably long time theonset of effect would take. In some embodiments, this delay in onset ofeffect with single-dose, intermittent doses or episodic use contributesto providing a butorphanol dosage form with lower abuse potential.

Without being bound by theory, at first glance, a major potentialconcern with some embodiments of the present invention (e.g., delayedonset, rapid release; or delayed onset, extended release; or delayedonset, pulsatile release; or duodenal release; or jejunal release; orileal release; or ileo-colonic release; or colonic release) would bewhether such compositions would provide continuous or around the clockplasma concentration and therapeutic effect, in view of the delayedrelease of drug following ingestion. In some embodiments, the inventiondeals with this issue in the following way: (i) oral butorphanolformulations whose release is delayed but subsequently immediate uponarriving at the target site in the lower segments of thegastrointestinal tract, the current dose would provide a therapeuticeffect until the next dose of the invention reaches the target site;(ii) oral butorphanol formulations whose release is delayed but wheninitiated it is subsequently further retarded at the target site(s) inthe lower segments of the gastrointestinal tract (e.g., controlledrelease, extended release or sustained release), the current dose wouldprovide a therapeutic effect until the next dose of the inventionreaches the target site. Thus, in some embodiments of the invention, theonly potential “therapeutic gap” of relates to the delay withtherapeutic effect with the initial or first dose of the drug. This maybe dealt with by using the dosage form of the drug in conventional orimmediate release form on a one time basis, or by use of an alternatedrug with the same or similar therapeutic effect or by limiting suchdosage forms to individuals requiring repeated or multiple dose therapy,time contingent therapy, treatment lasting more than a few days, orchronic therapy, or by excluding individuals requiring single doses,rapid onset of effect with the initial dose, intermittent dosing,episodic dosing. This potential “therapeutic gap” also provides for someof the abuse deterrent properties of the invention.

In some embodiments, the dosage form of the invention is a modifiedrelease oral formulation which, after an initial in vivo lag periodlasting at least about 1 hour, more preferably 1.5 hours, even morepreferably 2 hours, and most preferably 2.5 to 4 hours during whichthere is little or no release of butorphanol, rapidly releases (e.g.,over a period of less than about 1, 2 or 3 hours), most, substantiallyall or all of the butorphanol in vivo.

In some embodiments, the dosage form of the invention is a modifiedrelease oral formulation which, after an initial in vivo lag periodlasting at least about 1 hour, more preferably 1.5 hours, even morepreferably 2 hours, and most preferably 2.5 to 4 hours during whichthere is little or no release of butorphanol, gradually or slowlyreleases (e.g., over a period of not less than about 5, 7, 10, 12, 14,16, 18, 20, 21, 22, 23, 24, 28 or 30 hours), most, substantially all orall of the butorphanol in vivo.

In some embodiments, the dosage form of the invention is a modifiedrelease oral formulation which, after ingestion is characterized bylittle or no release of the butorphanol in the stomach, said dosage formreleases most, substantially all or all of the butorphanol from thedosage form in the duodenum, jejunum, ileum and/or colon, over a periodof less than about 1, 2 or 3 hours.

In some embodiments, the dosage form of the invention is a modifiedrelease oral formulation which, after ingestion is characterized bylittle or no release of the butorphanol in the stomach or duodenum, saiddosage form releases most, substantially all or all of the butorphanolfrom the dosage form upon arrival in the jejunum, ileum and/or colon,over a period of less than about 1, 2 or 3 hours.

In some embodiments, the dosage form of the invention is a modifiedrelease oral formulation which, after ingestion is characterized bylittle or no release of the butorphanol in the stomach, duodenum orjejunum, said dosage form releases most, substantially all or all of thebutorphanol from the dosage form upon arrival in the ileum and/or colon,over a period of less than about 1, 2 or 3 hours.

In some embodiments, the dosage form of the invention is a modifiedrelease oral formulation which, after ingestion is characterized bylittle or no release of the butorphanol in the stomach, duodenum,jejunum or ileum, said dosage form releases most, substantially all orall of the butorphanol from the dosage form upon arrival in the colon,over a period of less than about 1, 2 or 3 hours.

In some embodiments, the dosage form of the invention is a modifiedrelease oral formulation which, after ingestion is characterized bylittle or no release of the butorphanol in the stomach, said dosage formreleases most, substantially all or all of the butorphanol from thedosage form in the duodenum, jejunum, ileum and/or colon gradually overa period of not less than about 5, 7, 10, 12, 14, 16, 18, 20, 21, 22,23, 24, 28 or 30 hours.

In some embodiments, the dosage form of the invention is a modifiedrelease oral formulation which, after ingestion is characterized bylittle or no release of the butorphanol in the stomach or duodenum, saiddosage form releases most, substantially all or all of the butorphanolfrom the dosage form upon arrival in the jejunum, ileum and/or colongradually over a period of not less than about 5, 7, 10, 12, 14, 16, 18,20, 21, 22, 23, 24, 28 or 30 hours.

In some embodiments, the dosage form of the invention is a modifiedrelease oral formulation which, after ingestion is characterized bylittle or no release of the butorphanol in the stomach, duodenum orjejunum, said dosage form releases most, substantially all or all of thebutorphanol from the dosage form upon arrival in the ileum and/or colongradually over a period of not less than about 5, 7, 10, 12, 14, 16, 18,20, 21, 22, 23, 24, 28 or 30 hours.

In some embodiments, the dosage form of the invention is a modifiedrelease oral formulation which, after ingestion is characterized bylittle or no release of the butorphanol in the stomach, duodenum,jejunum or ileum, said dosage form releases most, substantially all orall of the butorphanol from the dosage form upon arrival in the colongradually over a period of not less than about 5, 7, 10, 12, 14, 16, 18,20, 21, 22, 23, 24, 28 or 30 hours.

In some embodiments, the described in vitro or in vivo (includinggastrointestinal tract and systemic) release characteristics,specifications and claims of the dosage forms of the invention areobserved after some, or most, or substantially all, or all administeredor ingested doses.

In some embodiments, the described pharmacokinetic and pharmacodynamiccharacteristics, specifications and claims of the dosage forms of theinvention are observed after some, or most, or substantially all, or alladministered or ingested doses.

In some embodiments, the described in vitro or in vivo (includinggastrointestinal tract and systemic) release characteristics,specifications and claims of the dosage forms of the invention areobserved after first administration.

In some embodiments, the described pharmacokinetic and pharmacodynamiccharacteristics, specifications and claims of the dosage forms of theinvention are observed after first administration.

In some embodiments, the described in vitro or in vivo (includinggastrointestinal tract and systemic) release characteristics,specifications and claims of the dosage forms of the invention areobserved after repeated or multiple administration.

In some embodiments, the described pharmacokinetic and pharmacodynamiccharacteristics, specifications and claims of the dosage forms of theinvention are observed after repeated or multiple administrations.

In some embodiments, the oral modified release butorphanol dosage formis coated, or sequestered so as to release little or no butorphanol inthe stomach, or stomach and duodenum, or stomach, duodenum and jejunum,or stomach, duodenum, jejunum and ileum, or stomach, duodenum, jejunum,ileum and ileo-cecal junction.

In some embodiments, the oral modified release butorphanol dosage formprovides an oral pharmaceutical composition and method of treating abutorphanol responsive medical condition, said treatment (i) achievingthe same therapeutic objectives with a reduced dose of butorphanol; (ii)providing improved dose proportional extent of absorption; (iii) a moreconsistent clinical effect; (iv) a more consistent pharmacokineticeffect; (v) more consistent extent of oral absorption; (vi) greaterefficacy; (vii) reduced frequency, duration and/or magnitude of sideeffects; (viii) reduced frequency, duration and/or magnitude of sideeffects at or for up to 0.5, 1, 2, 3, 4, 5, 6, 7 or 8 hours after thefirst dose; (ix) reduced frequency, duration and/or magnitude of nausea,vomiting and/or drowsiness; (x) reduced potential for drug abuse, drugdiversion, drug liking, and mood altering effects; (xi) reducedpotential for euphoria, drug liking, and mood altering effects; (xii)more efficient clinical management; (xiii) reduced metaboliteaccumulation (reduced metabolite to parent drug ratio), including insubjects with renal impairment; (xiv) reduced metabolite related sideeffects, e.g., neurotoxicity and myoclonus.

In some embodiments, the oral modified release butorphanol dosage formdemonstrate increased efficacy of at least about 1%, 2%, 3%, 4%, 5%, 6%,or 8%, 10%, 12%, 15%, 20%, 30%, or 40%, when compared with oralimmediate release dosage forms.

In some embodiments, the oral modified release butorphanol dosage formdemonstrate reduced euphoria, drug liking, mood altering effects,nausea, vomiting, blurred vision, fatigue and/or drowsiness of at leastabout 1%, 2%, 3%, 4%, 5%, 6%, or 8%, 10%, 12%, 15%, 20%, 30%, or 40%,when compared with oral immediate release dosage forms.

In some embodiments, the oral modified release butorphanol dosage formdemonstrate reduced euphoria, drug liking, mood altering effects,nausea, vomiting, blurred vision, fatigue and/or drowsiness of at leastabout 1%, 2%, 3%, 4%, 5%, 6%, or 8%, 10%, 12%, 15%, 20%, 30%, or 40%,when compared with intranasal dosage forms.

In some embodiments, the dosage form of the invention is an oral dosageform comprising: (i) a therapeutically effective amount of butorphanol,a pharmaceutically acceptable salt thereof, or a mixture thereof, and(ii) controlled release material to render said dosage form suitable formodified release, said dosage form providing butorphanol release distalto the duodenum, jejunum or ileum.

In some embodiments, the dosage form of the invention is an oral dosageform comprising: (i) a therapeutically effective amount of butorphanol,a pharmaceutically acceptable salt thereof, or a mixture thereof, and(ii) controlled release material to render said dosage form suitable formodified release, said dosage form providing butorphanol release distalto the stomach, duodenum, jejunum or ileum. said delayed releaserendering said dosage form abuse resistant.

In some embodiments, the dosage form of the invention is an oral dosageform comprising: (i) a therapeutically effective amount of butorphanol,a pharmaceutically acceptable salt thereof, or a mixture thereof, and(ii) controlled release material to render said dosage form suitable formodified release, said dosage form providing butorphanol release distalto the stomach, duodenum, jejunum or ileum, said dosage form havingreduced drug linking compared with oral dosage forms of butorphanolsuitable for modified release but without delayed release. In someembodiments, said modified release dose with delayed onset has at leastabout 10%, 20%, or 30%, or 40%, or 50%, or 60%, or 75%, or 100%, or150%, or 200%, or 250%, or 300% less drug liking than said comparatordose of modified release without delayed onset.

In some preferred embodiments, the controlled release material of theoral dosage form of the invention further comprises material to rendersaid composition resistant or substantially resistant to dissolution inthe stomach, or in the duodenum, or in the jejunum, or in the ileum, orin the small intestine, or in the stomach and duodenum, or in thestomach, duodenum and jejunum, or in the stomach, duodenum, jejunum andterminal ileum, in the stomach and small intestine, or before it reachesthe ileo-cecal junction, or until it crosses the ileo-cecal junction oruntil it reaches the colon.

In some preferred embodiments, the controlled release material of theoral dosage form of the invention further comprises an overcoat materialor an embedded material to render said composition resistant orsubstantially resistant to dissolution in the stomach, or in theduodenum, or in the jejunum, or in the ileum, or in the small intestine,or in the stomach and duodenum, or in the stomach, duodenum and jejunum,or in the stomach, duodenum, jejunum and terminal ileum, in the stomachand small intestine, or before it reaches the ileo-cecal junction, oruntil it crosses the ileo-cecal junction or until it reaches the colon.In some preferred embodiments, said overcoat is additionallyincorporated into or applied over immediate release dosage forms, andcontrolled release matrix dosage forms, including controlled porosityosmotic dosage forms, push pull osmotic dosage forms.

As used herein with respect to the butorphanol dosage form of theinvention, the term “oral”, “oral dosage form”, “oral pharmaceuticaldosage form”, “oral administration”, “oral compositions” “oralpharmaceutical compositions”, “oral tablets”, “oral capsules”, “orallyingested”, “orally”, “oral route” and the like all refer to any methodof administration through the mouth. The oral dosage form of theinvention is usually ingested intact, although it may be ingestedun-intact or tampered (e.g., crushed) and usually with the aid of wateror a beverage to hasten passage through the mouth. As used herein,“controlled release material”, “controlled release means”, and “materialto provide controlled release” means an in vitro or in vivo release ratecontrolling excipient or material incorporated in the dosage form whosefunction or primary function is to modify release (e.g, onset ofrelease, rate of release, duration of release) of an active drug (e.g.,butorphanol) from a dosage form or a portion (i.e., cause the dosageform to release in other than an immediate release fashion). Inpreferred embodiments of the invention, the controlled release materialfunctions to provide one or more of the following: (1) delay in theonset of release; (2) delay in the rate of release; (3) increase in theduration of release; (4) prolonged or extended duration of release; (5)pulsatile release; (6) delay in the onset of therapeutic effect; (7)delay in onset of side effects; (8) delay in the onset of psychic ormood altering effects; (9) reduced abuse liability; (10) prolonged orextended duration of therapeutic effect; (11) more robust therapeuticeffect; (12) a pharmacokinetic profile consistent with dosage formswhich are controlled release, extended release, sustained release,delayed onset, rapid release or delayed onset, extended release, ordelayed onset, pulsatile release, or modified release, or slow releaseor prolonged release; (13) a pharmacodynamic profile consistent withdosage forms which are controlled release, extended release, sustainedrelease, delayed onset, rapid release or delayed onset, extendedrelease, or delayed onset, pulsatile release, or modified release, orslow release or prolonged release (14) efficacy or improved efficacy bythe oral route; (15) improved safety by the oral route; (16) improvedefficiency of the dosage form; (17) improved dose proportional extent ofabsorption; (18) reduced variability in absorption; (19) providepulsatile release of the active drug; (20) provide delayed onset, rapidrelease of the dosage form; (21) provide delayed onset, extended releaseof the dosage form; (22) improved efficacy through delayed onset, rapidrelease or delayed onset, extended release compared with immediaterelease oral dosage forms; and (23) reduced potential for misuse, abuse,addiction and drug diversion.

In particularly preferred embodiments of the invention, the controlledrelease material functions to provide one or more of the following: (1)delay in the onset of release; (2) delay in the rate of release; (3)prolonged or extended duration of release; (4) delay in the onset oftherapeutic effect; (5) delay in onset of side effects; (6) delay in theonset of psychic or mood altering effects; (7) reduced abuse liability;(8) prolonged or extended duration of therapeutic effect; (9) improvedsafety by the oral route compared with the same dose intranasally; (10)improved dose proportional extent of absorption, compared with theintranasal butorphanol; (11) reduced variability in absorption; and (12)jejunal, ileal, ileo-colonic or colonic release

In some preferred nonlimiting examples, incorporation of controlledrelease material into the dosage form can provide for one or more of thefollowing: (1) delay in release for at least about 1 hour, morepreferably 1.5 hours, even more preferably 2 hours, and most preferably2.5 to 4 hours, where the onset of first release or first substantialrelease is delayed but after start of said release, most, substantiallyall, or all of the active drug is rapidly released or liberated from thedosage form; (2) delay in release for at least about 1 hour, morepreferably 1.5 hours, even more preferably 2 hours, and most preferably2.5 to 4 hours, where the onset of first release or first substantialrelease is delayed but after start of said release, the active drug israpidly released or liberated from the dosage form; (3) a delay inrelease, where, (a) the onset of first release or first substantialrelease is delayed until a specified or preferred time after oralingestion, preferably for at least about 1 hour, more preferably 1.5hours, even more preferably 2 hours, and most preferably 2.5 to 4 hours,or until the dosage form reaches a specified or preferred anatomiclocation in the GI lumen (preferably the duodenum, more preferably thejejunum and most preferably, the ileum or colon), or until the dosageform is in contact or prolonged contact with a preferred or specified invitro or in vivo (GI) environment (such pH, GI luminal osmotic pressure,dosage form osmotic pressure, hydration, microbial environment, level ofGI peristalsis or agitation), and (b) after the start of said release,most, substantially all, or all of the active drug is rapidly releasedor liberated from the dosage form (e.g., over a period of less thanabout 1, 2 or 3 hours); (4) a delay in release, where, (a) the onset offirst release or first substantial release is delayed until a specifiedor preferred time after oral ingestion (preferably a delay in releasefor at least about 1 hour, more preferably 1.5 hours, even morepreferably 2 hours, and most preferably 2.5 to 4 hours), and/or untilthe dosage form is in contact or prolonged contact with a particular invitro or in vivo (GI) pH, or until the dosage form is in contact orprolonged contact with a preferred or specified in vitro or in vivo (GI)environment (such pH, GI luminal osmotic pressure, dosage form osmoticpressure, hydration, microbial environment, level of GI peristalsis oragitation), and (b) after the start of said release, the active drug israpidly released or liberated from the dosage form (preferably over aperiod of less than about 1, 2 or 3 hours); (5) delay in release, wherethe onset of first release or first substantial release is delayed(preferably a delay in release for at least about 1 hour, morepreferably 1.5 hours, even more preferably 2 hours, and most preferably2.5 to 4 hours) but after start of said release, most, substantiallyall, or all of the active drug is slowly released or liberated from thedosage form; (6) delay in release, where the onset of first release orfirst substantial release is delayed (preferably over a period of lessthan about 1, 2 or 3 hours) but after start of said release, the activedrug is slowly released or liberated from the dosage form, over a periodof not less than about 5, 7, 10, 12, 14, 16, 18, 20, 21, 22, 23, 24, 28or 30 hours; (7) delayed onset, extended release, where, (a) the onsetof first release or first substantial release is delayed until aspecified or preferred time after oral ingestion (preferably a delay inrelease for at least about 1 hour, more preferably 1.5 hours, even morepreferably 2 hours, and most preferably 2.5 to 4 hours), or until thedosage form reaches a specified or preferred anatomic location in the GIlumen, or until the dosage form is in contact or prolonged contact witha preferred or specified in vitro or in vivo (GI) environment (such pH,GI luminal osmotic pressure, dosage form osmotic pressure, hydration,microbial environment, level of GI peristalsis or agitation), and (b)after the start of said release, most, substantially all, or all of theactive drug is slowly released or liberated from the dosage form (e.g,prolonged release, or extended release, or sustained release, or slowrelease, or release over a period of not less than about 5, 7, 10, 12,14, 16, 18, 20, 21, 22, 23, 24, 28 or 30 hours; (8) delayed onset, rapidrelease, where, (a) the onset of first release or first substantialrelease is delayed until a specified or preferred time after oralingestion (preferably a delay in release for at least about 1 hour, morepreferably 1.5 hours, even more preferably 2 hours, and most preferably2.5 to 4 hours), or until the dosage form reaches a specified orpreferred anatomic location in the GI lumen, or until the dosage form isin contact or prolonged contact with a preferred or specified in vitroor in vivo (GI) environment (such pH, GI luminal osmotic pressure,dosage form osmotic pressure, hydration, microbial environment, level ofGI peristalsis or agitation), and (b) after the start of said release,the active drug is rapidly released or liberated from the dosage form(preferably over a period of less than about 1, 2 or 3 hours); (8b)“delayed onset, pulsatile release”, where, (a) the onset of firstrelease or first substantial release is delayed until a specified orpreferred time after oral ingestion (preferably a delay in release forat least about 1 hour, more preferably 1.5 hours, even more preferably 2hours, and most preferably 2.5 to 4 hours), or until the dosage formreaches a specified or preferred anatomic location in the GI lumen, oruntil the dosage form is in contact or prolonged contact with apreferred or specified in vitro or in vivo (GI) environment (such pH, GIluminal osmotic pressure, dosage form osmotic pressure, hydration,microbial environment, level of GI peristalsis or agitation), and (b)after the start of said release, rapidly release the active drug fromthe dosage form in “pulses” at their desired time intervals (e.g, aboutevery 2, 3, 4, 5, 6, 8 or 12 hours), each pulse releasing a portion ofthe active drug rapidly (e.g., over about 0.125, 0.25, 0.5, 0.75, 1,1.5, 2, 2.5, 3, 3.5 hours from the desired time); (9) rapid onset offirst release or first substantial release, with continued slow releaseor liberation of the active drug from the dosage form; (10) slow onsetof first release or first substantial release, with continued slowrelease or liberation of the active drug from the dosage form; (11) slowonset of first release or first substantial release (preferably over aperiod of less than about 1, 2 or 3 hours), with continued slow releaseor liberation of the active drug from the dosage form over a period ofnot less than about 5, 7, 10, 12, 14, 16, 18, 20, 21, 22, 23, 24, 28 or30 hours; (12) no release or substantially no release in the stomach,followed by first release or first substantial release of the activedrug from the dosage form in the duodenum or distal to the duodenum,where, after start of said first release, the active drug is rapidlyreleased or liberated from the dosage form; (13) no release orsubstantially no release in the stomach, followed by first release orfirst substantial release of the active drug from the dosage form in theduodenum or distal to the duodenum, where, after start of said firstrelease, the active drug is slowly released or liberated from the dosageform; (14) no release or substantially no release in the stomach,followed by first release or first substantial release of the activedrug from the dosage form in the duodenum or distal to the duodenum,where, after start of said first release, the active drug is slowlyreleased or liberated from the dosage form over a period of not lessthan about 5, 7, 10, 12, 14, 16, 18, 20, 21, 22, 23, 24, 28 or 30 hours;(15) no release or substantially no release in the duodenum or proximalto the duodenum, followed by first release or first substantial releaseof the active drug from the dosage form in the jejunum or distal to thejejunum, where, after start of said first release, the active drug israpidly released or liberated from the dosage form; (16) no release orsubstantially no release in the duodenum or proximal to the duodenum,followed by first release or first substantial release of the activedrug from the dosage form in the jejunum or distal to the jejunum,where, after start of said first release, the active drug is slowlyreleased or liberated from the dosage form over a period of not lessthan about 5, 7, 10, 12, 14, 16, 18, 20, 21, 22, 23, 24, 28 or 30 hours;(17) no release or substantially no release in the jejunum or proximalto the jejunum, followed by first release or first substantial releaseof the active drug from the dosage form in the ileum and/or colon,where, after start of said first release, the active drug is rapidlyreleased or liberated from the dosage form; (18) no release orsubstantially no release in the jejunum or proximal to the jejunum,followed by first release or first substantial release of the activedrug from the dosage form in the ileum and/or colon, where, after startof said first release, the active drug is slowly released or liberatedfrom the dosage form over a period of not less than about 5, 7, 10, 12,14, 16, 18, 20, 21, 22, 23, 24, 28 or 30 hours; (19) no release orsubstantially no release in the ileum or proximal to the ileum, followedby first release or first substantial release of the active drug fromthe dosage form in the colon, where, after start of said first release,the active drug is rapidly released or liberated from the dosage form;(20) no release or substantially no release in the ileum or proximal tothe ileum, followed by first release or first substantial release of theactive drug from the dosage form in the colon, where, after start ofsaid first release, the active drug is rapidly released or liberatedfrom the dosage form, over a period of not less than about 5, 7, 10, 12,14, 16, 18, 20, 21, 22, 23, 24, 28 or 30 hours.

As used herein, the term “modified release” dosage forms meanpharmaceutical preparations which release an active ingredient from adosage form or a portion thereof in other than an immediate releasefashion. Modified release pharmaceutical compositions are usually madeby incorporating a controlled release material in the dosage form.Modified release pharmaceutical compositions are sometimes made also bydirect compression, wherein the compression force exceeds the usualcompression force for immediate release tablets. Modified release dosageforms are sometimes designed to accomplish pharmaceutical,pharmacokinetic, pharmacodynamic, therapeutic or convenience objectivesnot offered by conventional dosage forms such as a solution or animmediate release dosage form.

As used herein, the term “modified release” includes “delayed onset” (or“delayed release”) and “controlled release”.

As used herein, the term “modified release” also includes dosage formsthat provide “duodenal release”, “duodenal delivery”, “jejunal release”,“jejunal delivery”, “ileal release”, “ileal delivery”, “colonicrelease”, “colonic delivery”, “ileo-colonic release” and “ileo-colonicdelivery”.

As used herein, “controlled release” dosage forms mean pharmaceuticalpreparations which release an active ingredient from a dosage form or aportion thereof over an extended period of time (over a period of timegreater than 4 or 6 hours, preferably over for period of up to about 8hours, and most preferably for periods of up to about 12 hours or up toabout 24 hours, or longer, either with an initial delay in release(e.g., a delay of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5,7, 7.5 or 8 hours; preferably lasting at least about 1 hour, morepreferably 1.5 hours, even more preferably 2 hours, and most preferably2.5 to 4 hours) or without an initial delay in release.

As used herein, “controlled release” is used interchangeably with“prolonged release”, “slow release”, “sustained release”, “extendedrelease”, “retarded release”, “long acting” and the like.

As used herein, “delayed onset” and “delayed release” dosage forms meanpharmaceutical preparations which release begin the first release of anactive ingredient from a dosage form or a portion thereof (i) at timeother than immediately following oral administration; and/or (ii) aftera lag period lasting from minutes to hours (e.g., 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours; preferably lasting atleast about 1 hour, more preferably 1.5 hours, even more preferably 2hours, and most preferably 2.5 to 4 hours); and/or (iii) upon reachingthe desired or target GI anatomic location distal to the stomach (e.g.,distal to the stomach, duodenum, jejunum, ileum, ileo-cecal junction orcolon; preferably distal to the stomach, more preferably distal to theduodenum, and most preferably distal to the jejunum or ileum) or GIenvironment distal to the stomach (e.g., pH at the point of release,osmotic pressure at the point of release, hydration, microbial flora).Delayed onset formulations of the invention may be delayed onset, rapidrelease; delayed onset, pulsatile release; or delayed onset, extendedrelease.

As used herein, “delayed onset, rapid release” means dosage forms whichafter a desired lag period post-ingestion (e.g., 0.5, 1, 1.5, 2, 2.5, 3,3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours; preferably lasting atleast about 1 hour, more preferably 1.5 hours, even more preferably 2hours, and most preferably 2.5 to 4 hours), rapidly releases (i.e., overabout 0.05, 0.1, 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 hours;preferably over a period of less than about 1, 2 or 3 hours)substantially all or all the active drug from the dosage form.

As used herein, “delayed onset, pulsatile release” means dosage formswhich after a desired lag period post-ingestion (e.g., 0.5, 1, 1.5, 2,2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours; preferablylasting at least about 1 hour, more preferably 1.5 hours, even morepreferably 2 hours, and most preferably 2.5 to 4 hours), rapidlyreleases (i.e., over about 0.05, 0.1, 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2,2.5, 3, 3.5 hours; preferably over a period of less than about 1, 2 or 3hours) some of the active drug from the dosage form in “pulses” at thedesired time intervals (e.g, about every 1, 2, 3, 4, 5, 8, or 12 hours),each pulse releasing a portion of the active drug in the dosage form.

As used herein, “delayed onset, extended release” means dosage formswhich after a desired lag period post-ingestion (e.g., 0.5, 1, 1.5, 2,2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours; preferablylasting at least about 1 hour, more preferably 1.5 hours, even morepreferably 2 hours, and most preferably 2.5 to 4 hours), slowly releasethe active drug from the dosage form over an extended period of time,over a period of not less than about 5, 7, 10, 12, 14, 16, 18, 20, 21,22, 23, 24, 28 or 30 hours.

As used herein, “delayed release” and “delayed onset” include dosageforms which are delayed onset, rapid release; delayed onset, pulsatilerelease; and delayed onset.

In some embodiments, one or more, or substantially all, or all of theembodiments and specifications showing benefit or a difference formodified release delayed onset dosage forms of oral butorphanol (e.g.,delayed onset, rapid release; delayed onset, pulsatile release; delayedonset, extended release) over immediate release oral butorphanol, thephrase “immediate release” may be substituted with “controlled release”,“extended release”, “sustained release” or “pulsatile release”, providedsaid controlled release, extended release or pulsatile release dosageforms are not delayed onset dosage forms.

In some embodiments, one or more, or substantially all, or all of theembodiments and specifications showing benefit or a difference fordelayed onset dosage forms of oral butorphanol (e.g., delayed onset,rapid release; delayed onset, pulsatile release; delayed onset, extendedrelease) over intranasal butorphanol, “intranasal” dosage forms ofbutorphanol may be substituted with oral “immediate release” dosageforms of butorphanol.

In some embodiments, one or more, or substantially all, or all of theembodiments and specifications showing benefit or a difference fordelayed onset dosage forms of oral butorphanol (e.g., delayed onset,rapid release; delayed onset, pulsatile release; delayed onset, extendedrelease) over intranasal butorphanol, “intranasal” dosage forms ofbutorphanol may be substituted with oral “immediate release” dosageforms of butorphanol.

In some embodiments, controlled release dosage forms of the presentinvention releases butorphanol from the oral dosage form at a slowerrate than immediate release formulations. In some preferred embodiments,extended release dosage forms and delayed onset, extended release dosageforms release butorphanol at such a rate that plasma concentrationsand/or therapeutic effects are maintained within the therapeutic range(above the minimum effective therapeutic concentration) but below toxiclevels for intended duration (e.g., over a period of about 6 to about 30hours, preferably over a period of time indicative of a Q8H, Q8H PRN,Q12H, Q12H PRN, Q24H or Q24H PRN administration, more preferably over aperiod of time indicative of a Q12H, Q12H PRN, Q24H or Q24H PRNadministration). In some preferred embodiments, the extended releaseformulations of the present invention provide therapeutic effects for aduration that is longer or substantially longer than the duration ofmeaningful or detectable plasma concentrations of butorphanol.

When applied to the present invention, present invention, the term“immediate release”, “immediate release dosage forms”, “immediaterelease composition”, “immediate release tablet”, “immediate releasecapsule”, “immediate release formulation”, immediate release forms” andthe like is a dosage form which is formulated to release the active drugfrom the dosage form immediately (i.e., without an attempt to delay orprolong the release of the active drug from the dosage form as is thecase, for example, with extended release dosage forms) or a dosage formwhich allows the drug to dissolve in the gastrointestinal contents, withno intention of delaying or prolonging the dissolution or absorption ofthe drug). Immediate release dosage forms may be in any form, includingtablet, capsule, solution, suspension, powder, micronized, granulatedetc. When applied to butorphanol dosage forms of the invention, unlessfurther modified to alter the meaning, “immediate release” refers tooral dosage forms. In the absence of a commercially available oralimmediate release butorphanol product, an available parenteral orintranasal formulation of butorphanol or a salt thereof may be usedorally, or a solution of butorphanol or a salt thereof may be preparedor an immediate release tablet may be prepared for the purpose of invivo testing requiring immediate release butorphanol. Alternatively, animmediate release formulation of butorphanol may be prepared byencapsulating liquid or uncompressed solid butorphanol, or bycompressing butorphanol into tablet form without excipients or materialthat impart a delay or retardation to its release. Immediate releasedosage forms generally disintegrate in ≦about 0.5 hours or ≦about 1hour, and generally substantially or completely dissolve in ≦about 0.25,or ≦about 0.5, or ≦about 0.75, or ≦about 1 or ≦about 1.25, or ≦about1.5, or ≦about 1.75, or ≦about 2 hours, when measured by the recommendedor appropriate USP compendial methods (for example some dosage forms maybe tested by USP Basket Method or USP Paddle Method at 100 rpm in 900 mLof water at 37° C.).

As used herein, “intranasal” dosage forms of butorphanol refer to acommercially available intranasal formulation of butorphanol listed inFDA's Orange Book, preferably the reference listed product, and in itsabsence, a listed A/B generic product. In the absence of such a product,alternative intranasal formulations may be substituted (for example,commercially available intranasal formulations are listed non-A/Bgeneric products in the USA, formulation approved by the EMEA oravailable in the European Union, or formulations listed in Martindale:The Complete Drug Reference, 35th Edition [or more recent],Pharmaceutical Press), or in the absence of a suitable alternative, anextemporaneously compounded solution suitable for intranasaladministration may be prepared.

When commercially available immediate release oral dosage forms ofbutorphanol are not available, they may be made or extemporaneouslycompounded in the forms of powder, solution, suspension, tablets,uncompressed capsules or tablets, each devoid of controlled releasematerial.

For purposes of the invention, the oral modified release and oralimmediate release formulations are dose proportional. In suchformulations, the pharmacokinetic parameters (e.g., AUC and C_(max))generally increase linearly from one dosage strength to another.Therefore the pharmacokinetic parameters of a particular dose can beinferred from the parameters of a different dose of the sameformulation.

As used herein with respect to the butorphanol dosage form of theinvention, “duodenal release” and “duodenal delivery” areinterchangeable and refer to in vivo release of all, substantially allor most butorphanol from the dosage form into the portion ofgastrointestinal tract distal to the stomach. In some embodiments,duodenal release or duodenal delivery dosage forms of the inventionprovide in vivo release of all, substantially all or most butorphanolfrom the dosage form rapidly upon reaching the portion ofgastrointestinal tract distal to the stomach. In other embodiments,duodenal release and duodenal delivery dosage forms of the inventionprovide in vivo release of all, substantially all or most butorphanolfrom the dosage form slowly (e.g., sustained release or extendedrelease) upon reaching the portion of gastrointestinal tract distal tothe stomach.

As used herein with respect to the butorphanol dosage form of theinvention, “jejunal release” and “jejunal delivery” are interchangeable,and refers to in vivo release of all, substantially all or mostbutorphanol from the dosage form into the portion of gastrointestinaltract distal to the duodenum. In some embodiments, jejunal release” or“jejunal delivery dosage forms of the invention provide in vivo releaseof all, substantially all or most butorphanol from the dosage formrapidly upon reaching the portion of gastrointestinal tract distal tothe duodenum. In other embodiments, duodenal release and duodenaldelivery dosage forms of the invention provide in vivo release of all,substantially all or most butorphanol from the dosage form slowly (e.g.,sustained release or extended release) upon reaching the portion ofgastrointestinal tract distal to the duodenum.

As used herein with respect to the butorphanol dosage form of theinvention, “ileal release” and “ileal delivery” are interchangeable andrefers to in vivo release of all, substantially all or most butorphanolfrom the dosage form into the portion of gastrointestinal tract distalto the jejunum. In some embodiments, ileal release or ileal deliverydosage forms of the invention provide in vivo release of all,substantially all or most butorphanol from the dosage form rapidly uponreaching the portion of gastrointestinal tract distal to the jejunum. Inother embodiments, ileal release and ileal delivery dosage forms of theinvention provide in vivo release of all, substantially all or mostbutorphanol from the dosage form slowly (e.g., sustained release orextended release) upon reaching the portion of gastrointestinal tractdistal to the jejunum.

As used herein with respect to the butorphanol dosage form of theinvention, “ileo-colonic release” and “ileo-colonic delivery” areinterchangeable and are interchangeable and refer to in vivo release ofall, substantially all or most butorphanol from the dosage form into theportion of gastrointestinal tract distal to the jejunum and/or distal tothe ileum. In some embodiments, ileo-colonic release or ileo-colonicdelivery dosage forms of the invention provide in vivo release of all,substantially all or most butorphanol from the dosage form rapidly uponreaching the portion of gastrointestinal tract distal to the jejunum ordistal to the ileum. In other embodiments, ileo-colonic release andileo-colonic delivery dosage forms of the invention provide in vivorelease of all, substantially all or most butorphanol from the dosageform slowly (e.g., sustained release or extended release) upon reachingthe portion of gastrointestinal tract distal to the jejunum or distal tothe ileum.

As used herein with respect to the butorphanol dosage form of theinvention, “colonic release” and “colonic delivery” are interchangeableand refer to in vivo release of all, substantially all or mostbutorphanol from the dosage form into the portion of gastrointestinaltract distal to the ileum. In some embodiments, colonic release andcolonic delivery dosage forms of the invention provide in vivo releaseof all, substantially all or most butorphanol from the dosage formrapidly upon reaching the portion of gastrointestinal tract distal tothe ileum. In other embodiments, colonic release and colonic deliverydosage forms of the invention provide in vivo release of all,substantially all or most butorphanol from the dosage form slowly (e.g.,sustained release or extended release) upon reaching the portion ofgastrointestinal tract distal to the ileum.

Duodenal delivery, jejunal delivery, ileal delivery, ileo-colonicdelivery or colonic delivery dosage forms may be in the form of delayedonset, rapid release; delayed onset, pulsatile release; or delayed onsetextended release dosage forms

The term “optionally a controlled release material” means that thedosage may or may not be require one or more controlled release materialto achieve some, most, substantially all or all of the objectives,specifications or claims of the invention.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition for the treatment of a butorphanol responsivemedical condition comprising a therapeutically effective amount ofbutorphanol or pharmaceutically acceptable salts thereof or mixturethereof, and optionally a controlled release material, said butorphanolgiven alone or in combination with another drug in the same dosage formor in a different dosage form to treat the same or a different conditionor to treat side effects of butorphanol or to deter abuse of thebutorphanol.

In some preferred embodiments, the dosage form provides a pharmaceuticaldosage form for the treatment of a butorphanol responsive medicalcondition comprising a therapeutically effective amount of butorphanolor pharmaceutically acceptable salts thereof or mixture thereof, saiddosage form resistant or substantially resistant to dissolution and/orabsorption in the stomach, and/or in the duodenum, and/or in thejejunum, and/or in the ileum, or in the small intestine, or in thestomach and duodenum, or in the stomach, duodenum and jejunum, or in thestomach, duodenum, jejunum and terminal ileum, or in the stomach andsmall intestine, or before it reaches the ileo-cecal junction, or untilit crosses the ileo-cecal junction, or until it reaches the colon; saidbutorphanol in the dosage form released rapidly or slowly upon reachinga the desired anatomic region of the GI tract (e.g., ileum or colon) orupon reaching the desired gastrointestinal conditions conducive torelease from the dosage form (e.g., osmotic pressure, pH, time afteringestion, microbial flora); said dosage form in some embodimentsproviding immediate release of butorphanol following the expected lagtime; said dosage form in some other embodiments providing sustainedrelease of butorphanol following the expected lag time.

In some embodiments, the oral butorphanol dosage form is substantiallynon-releasable in the stomach and small intestine, or substantiallynon-releasable in the stomach and duodenum, or substantiallynon-releasable in the stomach, duodenum and jejunum, or substantiallynon-releasable in the stomach, duodenum, jejunum and terminal ileum, orsubstantially non-releasable until it reaches the ileum, orsubstantially non-releasable until it reaches the colon.

In some embodiments, the oral butorphanol dosage form is substantiallynon-releasable until up to about 1, or 1.5, 2, or 2.25, or 2.5, or 2.75,or 3, or 3.25, or 3.5, or 3.75, or 4, or 4.25, or 4.5, or 4.75, or 5, or5.25, or 5.5, or 5.75, or 6, or 6.25, or 6.5, or 7.75, or 7, or 7.25, or7.5, or 7.75, or 8, or 8.25, or 8.5, or 8.75, or 9, or 9.25, or 9.5, or9.75, or 10, or 10.25, or 10.5, or 10.75, or 11, or 11.25, or 1.5, or11.75, or 12, or 14, or 16, or 18, or 20 hours after oral ingestion ofthe oral dosage form. In some particularly preferred embodiments, saiddosage form is substantially non-releasable until up to about 2.5, or2.75, or 3, or 3.25, or 3.5, or 3.75, or 4, or 4.25, or 4.5, or 4.75, or5, or 5.25, or 5.5, or 5.75, or 6, or 6.25, or 6.5, or 7.75, or 7 hoursafter oral ingestion of the oral dosage form.

In some preferred embodiments, the oral butorphanol dosage form includesa coated capsule or tablet wherein the coating comprises material whichdissolves at a pH≧5, or ≧5.5, or ≧5.7, or ≧6, or ≧6.2, or ≧6.4, or ≧6.6,or ≧6.8, ≧7, or ≧7.2. In some other preferred embodiments, the oralbutorphanol dosage form includes material incorporated in dosage form,wherein the material substantially resists dissolution for at leastabout 1, or 1.5, or 2, or 2.5, or 3, or 3.25, or 3.5, or 3.75, or 4, or4.25, or 4.5, or 4.75, or 5, or 5.25, or 5.5, or 5.75, or 6, or 6.25, or6.5, or 7.75, or 7.31 hours at a pH of about ≦5, or ≦5.5, or ≦5.7, or≦6, or ≦6.2, or ≦6.4, or ≦6.6, or ≦6.8, ≦7, or ≦7.2.

In some embodiments, the oral butorphanol dosage form is coated with orincludes incorporated one or more of the following: (i) celluloseacetate trimellitiate (CAT); (ii) hydroxypropylmethyl cellulosephthalate (HPMCP); (iii) polyvinyl acetate phthalate (PVAP); (iv)shellac; (v) a copolymer of methacrylic acid and methylmethacrylate;(vi) a material which is redox-sensitive; (vii) an azopolymer or adisulphide polymer; (viii) a material which is degraded by enzymes orbacteria present in the colon; (ix) a copolymer of methacrylic acid andmethylmethacrylate to which has been added during polymerization themonomer methyl acrylate; (x) a cellulose ester; (xi) polyvinyl acetatephthalate.

In some embodiments, the dosage form consists of a coated capsulewherein the coating is applied separately to empty capsule body and cap.In some embodiments, the dosage form consists of a coated capsule filledwith a caplet or tablet.

In some embodiments, the oral butorphanol dosage form is non-releasingor substantially non-releasing for up to about 2, 2.5, 3, 3.5, 4, 4.5,or 5 hours following ingestion.

In some embodiments, the oral butorphanol dosage form comprises materialwhich is non-dissolving or substantially non-dissolving at a particularpH or range of pH and is dissolving or substantially dissolving atanother pH or another range of pH, said material commingled with thebutorphanol API or with the granulation containing butorphanol API.

In some embodiments, the oral butorphanol dosage form comprises materialwhich is non-dissolving or substantially non-dissolving at a particularpH or range of pH and is dissolving or substantially dissolving atanother pH or another range of pH, said material commingled with thebutorphanol API or with the granulation containing butorphanol API, inaddition to being coated on the dosage form.

In some embodiments, the specifications regarding coating of the dosageform of the invention with controlled release material or pH sensitivematerial are also applicable to dosage forms where said material iscommingled with the butorphanol API or with the granulation containingbutorphanol API, instead of or in addition to coating the dosage form.

In some embodiments, the specifications regarding coating of the dosageform of the invention with controlled release material or pH sensitivematerial are also applicable to dosage forms where is the coating isapplied to multiparticulate matrices or to subunits of the dosage forme.g., beads incorporating drug), instead of or in addition to coatingthe dosage form.

In some embodiments, the dosage form consists of a coated capsulewherein the coating is applied to capsules having a sealing on the gapbetween capsule body and cap.

In some embodiments, the dosage form consists of a coated capsulecontaining a butorphanol, wherein the capsule is coated with a materialselected from the group comprising cellulose acetate trimellitiate,hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate,shellac, and a copolymer of methacrylic acid and ethyl acrylate,azopolymers, disulphide polymers and amylose.

In some preferred embodiments, the oral butorphanol dosage form has abutorphanol Tmax that exceeds its dosing frequency.

In some preferred embodiments, the butorphanol Tmax ratio of the oralbutorphanol dosage form of the invention to butorphanol given orally asa conventional solution, suspension, immediate release tablet or capsuleor given intranasally is ≧1.25, or ≧1.5, or ≧1.75, or ≧2, or ≧2.5, or≧3, or ≧3.5, or ≧4, or ≧4.5, or ≧5, or ≧5.5, or ≧6, or ≧6.5, or ≧7, or≧7.5, or ≧8, or ≧8.5, or ≧9, or ≧9.5, or ≧10, or ≧10.5, or ≧12, or ≧14,or ≧16, or ≧18, or ≧20.

In some preferred embodiments, the hydroxybutorphanol T_(max) ratio ofthe oral butorphanol dosage form of the invention to butorphanol givenorally as a conventional solution, suspension, immediate release tabletor capsule or given intranasally is ≧1.25, or ≧1.5, or ≧1.75, or ≧2, or≧2.5, or ≧3, or ≧3.5, or ≧4, or ≧4.5, or ≧5, or ≧5.5, or ≧6, or ≧6.5, or≧7, or ≧7.5, or ≧8, or ≧8.5, or ≧9, or ≧9.5, or ≧10, or ≧10.5, or ≧12,or ≧14, or ≧16, or ≧18, or ≧20.

In some preferred embodiments, the butorphanol Cmax ratio afterbutorphanol given orally as a conventional solution, suspension,immediate release tablet or capsule, or given intranasally, to the oralbutorphanol dosage form of the invention given orally is ≧1.1, or ≧1.2,or ≧1.3, or ≧1.5, or ≧1.5, or ≧1.6, or ≧1.7, or ≧1.8, or ≧1.9, or ≧2, or≧2.2, or ≧2.5, or ≧3, or ≧3.5, or ≧4, or ≧4.5, or ≧5, or ≧5.5, or ≧6, or≧6.5, or ≧7, or ≧7.5, or ≧8, or ≧8.5, or ≧9, or ≧9.5, or ≧10, or ≧10.5,or ≧12, or ≧14, or ≧16, or ≧18, or ≧20.

In some preferred embodiments, the hydroxybutorphanol Cmax ratio ofbutorphanol given orally as a conventional solution, suspension,immediate release tablet or capsule, or given intranasally, to the oralbutorphanol dosage form of the invention given orally is ≧1.1, or ≧1.2,or ≧1.3, or ≧1.5, or ≧1.5, or ≧1.6, or ≧1.7, or ≧1.8, or ≧1.9, or ≧2, or≧2.2, or ≧2.5, or ≧3, or ≧3.5, or ≧4, or ≧4.5, or ≧5, or ≧5.5, or ≧6, or≧6.5, or ≧7, or ≧7.5, or ≧8, or ≧8.5, or ≧9, or ≧9.5, or ≧10, or ≧10.5,or ≧12, or ≧14, or ≧16, or ≧18, or ≧20.

In some preferred embodiments, the butorphanol AUC₀₋₂₄ ratio of the oralbutorphanol dosage form of the invention to butorphanol given orally asa conventional solution, suspension, immediate release tablet or capsuleis ≧1.1, or ≧1.2, or ≧1.3, or ≧1.5, or ≧1.5, or ≧1.6, or ≧1.7, or ≧1.8,or ≧1.9, or ≧2, or ≧2.2, or ≧2.5, or ≧3.

In some preferred embodiments, the butorphanol AUC_(0-inf) ratio of theoral butorphanol dosage form of the invention to butorphanol givenorally as a conventional solution, suspension, immediate release tabletor capsule is ≧1.1, or ≧1.2, or ≧1.3, or ≧1.5, or ≧1.5, or ≧1.6, or≧1.7, or ≧1.8, or ≧1.9, or ≧2, or ≧2.2, or ≧2.5, or ≧3.

In some preferred embodiments, the hydroxybutorphanol AUC₀₋₂₄ ratio ofthe oral butorphanol dosage form of the invention to butorphanol givenorally as a conventional solution, suspension, immediate release tabletor capsule is ≧1.1, or ≧1.2, or ≧1.3, or ≧1.5, or ≧1.5, or ≧1.6, or≧1.7, or ≧1.8, or ≧1.9, or ≧2, or ≧2.2, or ≧2.5, or ≧3.

In some preferred embodiments, the hydroxybutorphanol AUC_(0-inf) ratioof the oral butorphanol dosage form of the invention to butorphanolgiven orally as a conventional solution, suspension, immediate releasetablet or capsule is ≧1.1, or ≧1.2, or ≧1.3, or ≧1.5, or ≧1.5, or ≧1.6,or ≧1.7, or ≧1.8, or ≧1.9, or ≧2, or ≧2.2, or ≧2.5, or ≧3.

In some preferred embodiments, the apparent oral clearance ratio ofbutorphanol given orally as a conventional solution, suspension,immediate release tablet or capsule, to the oral butorphanol dosage formof the invention given orally is ≧1.1, or ≧1.2, or ≧1.3, or ≧1.4, or≧1.5.

In some embodiments, the oral modified release butorphanol dosage formreleases 0%, or less than about 0.1%, or 0.5%, or 1%, or 1.5%, or 2%, or2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or 5%, or 6%, or 7%, or 8%, or 9%,or 10%, or 12%, or 14%, or 15%, or 16%, or 17%, or 18%, or 20% or 25% or28% or 30% or 35% of butorphanol in vivo from the dosage form prior toreaching the duodenum, or jejunum, or ileum, or terminal ileum, orileo-cecal junction, or ascending colon, or transverse colon, ordescending colon, or colon

In some embodiments, the oral modified release butorphanol dosage formreleases 0%, or less than about 0.1%, or 0.5%, or 1%, or 1.5%, or 2%, or2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or 5%, or 6%, or 7%, or 8%, or 9%,or 10%, or 12%, or 14%, or 15%, or 16%, or 17%, or 18%, or 20% or 25% or28% or 30% or 35% of butorphanol in vivo from the dosage form for atleast about 1 hour, or at least about 1.5 hours, or at least about 2hours, or at least about 2.5 hours, or at least about 3 hours, or atleast about 3.25 hours, or at least about 3.5 hours, or at least about3.75 hours, or at least about 4 hours, or at least about 4.25 hours, orat least about 4.5 hours, or at least about 4.75 hours, or at leastabout 5 hours, or at least about 5.25 hours, or at least about 5.5hours, or at least about 5.75 hours, or at least about 6 hours, or atleast about 6.25 hours, or at least about 6.5 hours, or at least about6.75 hours, or at least about 7 hours, or at least about 7.25 hours, orat least about 7.5 hours, or at least about 7.75 hours, or at leastabout 8 hours, or at least about 8.25 hours, or at least about 8.5hours, or at least about 8.75 hours, or at least about 9 hours, or atleast about 9.25 hours, or at least about 9.5 hours, or at least about9.75 hours, or at least about 10 hours, or at least about 10.25 hours,or at least about 10.5 hours, or at least about 10.75 hours, or at leastabout 11 hours, or at least about 11.5 hours, or at least about 12 hoursafter oral ingestion, said in vivo release from the dosage form measuredby appearance of butorphanol in plasma, using AUC_(0-n)/AUC_(0-inf), orAUC_(0-n)/AUC_(0-τ), where “n” is the time after oral ingestion. Mostpreferably, the time after oral ingestion is at least about 2 hours, orat least about 2.5 hours, or at least about 3 hours, or at least about3.5 hours, or at least about 4 hours, or at least about 4.5 hours, or atleast about 5 hours, or at least about 5.5 hours, or at least about 6hours, or at least about 6.5 hours, or at least about 7 hours.

In some embodiments, the oral modified release butorphanol dosage formreleases 0%, or less than about 0.1%, or 0.5%, or 1%, or 1.5%, or 2%, or2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or 5%, or 6%, or 7%, or 8%, or 9%,or 10%, or 12%, or 14%, or 15%, or 16%, or 17%, or 18%, or 20% or 25% or28% or 30% or 35% of butorphanol in vivo from the dosage form when theaverage measured or expected gastrointestinal pH is less than about 3.5,or is less than about 4, or is less than about 4.5, or is less thanabout 5, or less than about 5.2, or less than about 5.4, or less thanabout 5.6, or less than about 5.8, or less than about 6, or less thanabout 6.2, or less than about 6.4, or less than about 6.5, or less thanabout 6.6, or less than about 6.7, or less than about 6.8, or less thanabout 6.9, or less than about 7, or less than about 7.1, or less thanabout 7.2, when measured up to about 1 hour, or up to about 1.5 hours,or up to about 2 hours, or up to about 2.5 hours, or up to about 2.75hours, or up to about 3 hours, or up to about 3.25 hours, or up to about3.5 hours, or up to about 3.75 hours, or up to about 4 hours, or up toabout 4.25 hours, or up to about 4.5 hours, after oral ingestion. Morepreferably, the dosage form releases 0%, or less than about 0.1%, or0.5%, or 1%, or 1.5%, or 2%, or 2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or5%, or 6%, or 7%, or 8%, or 9%, or 10%, or 12%, or 14%, or 15%, or 16%,or 17%, or 18%, or 20% or 25% or 28% or 30% or 35% of butorphanol invivo when the measured or expected gastrointestinal pH is less thanabout 5, or less than about 5.5, or less than about 6, or less thanabout 6.5, or less than about 6.8. More preferably, said release ismeasured at about 2 hours, or about 2.5 hours, or about 3 hours, or 4hours.

In some embodiments, the targeted gastrointestinal delivery of thebutorphanol from the oral modified release butorphanol dosage form intothe lower segments of the gastrointestinal tract can be achieved througha variety of approaches, including but limited to incorporation ofmaterial or processes to achieve one or more of the following:time-controlled, pH-controlled, pressure-controlled, enzyme-controlledand hydration-controlled. Since the gastrointestinal tract is a complex,variable and highly dynamic environment and further complicated by thevolume, content and location of food and beverages, in some embodiments,incorporation of material to achieve more than one of the aboveapproaches is preferred.

In some embodiments, the targeted gastrointestinal delivery of thebutorphanol from the oral modified release butorphanol dosage form intothe lower segments of the gastrointestinal tract can be achieved throughencapsulation of the butorphanol, preferably with excipients orfunctional excipients, said capsule incorporating, coated with orovercoated with material or processes to achieve targetedgastrointestinal delivery.

In some embodiments, the oral modified release butorphanol dosage formis non-bioavailable or substantially non-bioavailable for up to about0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 hours after oral ingestion(e.g., the dosage form releases 0%, or less than about 0.1%, or 0.5%, or1%, or 1.5%, or 2%, or 2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or 5%, or6%, or 7%, or 8%, or 9%, or 10%, or 12%, or 14%, or 15%, or 16%, or 17%,or 18%, or 20% or 25% or 28% or 30% or 35% of butorphanol in vivo whenassessed up to the specified time). In some embodiments, the oralmodified release butorphanol dosage form is coated with a material orincorporates material which renders the dosage form non-bioavailable orsubstantially non-bioavailable for up to about 0.5, 1, 1.5, 2, 2.5, 3,3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours; preferably at leastabout 1 hour, more preferably 1.5 hours, even more preferably 2 hours,and most preferably 2.5 to 4 hours.

Some or all of the above objects and others are achieved by embodimentsof the present invention, which is directed in part to a dosage form oforally administered butorphanol.

In some preferred embodiments, the invention comprises an oralpharmaceutical composition for the treatment of diseases and disorderscomprising a therapeutically effective amount of a butorphanol or apharmaceutically acceptable salt thereof or a mixture thereof.

In some embodiments, the invention provides modified release oralpharmaceutical compositions of butorphanol for the treatment of diseasesand disorders, said compositions in modified release form, said dosageform releasing 0%, or less than about 0.1%, or 0.5%, or 1%, or 1.5%, or2%, or 2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or 5%, or 6%, or 7%, or 8%,or 9%, or 10%, or 12%, or 14%, or 15%, or 16%, or 17%, or 18%, or 20% or25% or 28% or 30% or 35% of butorphanol in vivo from the dosage formprior to reaching the duodenum, or jejunum, or ileum, or terminal ileum,or ileo-cecal junction, or ascending colon, or transverse colon, ordescending colon, or colon.

In some embodiments, the invention provides modified release oralpharmaceutical compositions of butorphanol for the treatment of diseasesand disorders, said compositions in modified release form, said dosageform releasing most, substantially all or all of the releasablebutorphanol in the lower segment of the gastrointestinal tract (e.g.,distal to the duodenum, or jejunum, or ileum, or terminal ileum, orileo-cecal junction, ascending colon, or transverse colon), said releaseoccurring over about 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 30, 32, 36 or 40 hours.

In some embodiments, the invention provides modified release oralpharmaceutical compositions of butorphanol for the treatment of diseasesand disorders, said compositions in modified release form, said dosageform releasing most, substantially all or all of the releasablebutorphanol in the lower segment of the gastrointestinal tract (e.g.,distal to the duodenum, or jejunum, or ileum, or terminal ileum, orileo-cecal junction, ascending colon, or transverse colon), said releaseoccurring over about 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 or 4 hours.

In some embodiments, the invention provides modified release oralpharmaceutical compositions of butorphanol for the treatment of diseasesand disorders, said composition in modified, controlled, sustained orextended release form, said dosage form releasing 0%, or less than about0.1%, or 0.5%, or 1%, or 1.5%, or 2%, or 2.5%, or 3%, or 3.5%, or 4%, or4.5%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or 12%, or 14%, or 15%,or 16%, or 17%, or 18%, or 20% or 25% or 28% or 30% or 35% ofbutorphanol proximal to the duodenum, or jejunum, or ileum, or terminalileum, or ileo-cecal junction.

In some embodiments, the invention provides modified release oralpharmaceutical compositions of butorphanol for the treatment of diseasesand disorders, said composition in modified, controlled, sustained orextended release form, or for delivery distal to the duodenum, orjejunum, or ileum, or terminal ileum, or ileo-cecal junction, saiddosage form containing up to about 50%, or up to about 45%, or up toabout 40%, or up to about 35%, or up to about 30%, or up to about 25%,or up to about 20%, or up to about 15%, or up to about 10%, or up toabout 5% of the butorphanol dose in immediate release form, saidimmediate release form released and/or available for absorption in thestomach, duodenum, jejunum and/or ileum, and said immediate release formreleased and/or available for absorption at a pH of less than about 1,or less than about 1.5, or less than about 2, or less than about 2.5, orless than about 3, or less than about 3.5, or less than about 4, or lessthan about 4.5, or less than about 5, or less than about 5.5, or lessthan about 6, or less than about 7.

It is an object of certain preferred embodiments of the presentinvention to provide oral extended release pharmaceutical compositionsof butorphanol that have greater bioavailability (AUC) than oralimmediate release formulations.

It is an object of certain preferred embodiments of the presentinvention to provide oral immediate release and oral extended releasepharmaceutical compositions of butorphanol that provide a greater plasmaAUC ratio of hydroxybutorphanol (a major metabolite of butorphanol) tobutorphanol than is attained by intranasally administered dosage forms.

It is an object of certain preferred embodiments of the presentinvention to provide oral immediate release and oral extended releasepharmaceutical compositions of butorphanol that provide a greater plasmaAUC ratio of hydroxybutorphanol to butorphanol than is attained byintranasally administered dosage forms.

Some or all of the above objects and others are achieved by embodimentsof the present invention, which is directed in part to a dosage form oforal butorphanol.

In certain preferred embodiments the oral dosage form of the presentinvention comprises a matrix which includes a sustained release materialand butorphanol or a pharmaceutically acceptable salt thereof. Incertain preferred embodiments, the matrix is compressed into a tabletand may be optionally overcoated with a coating that in addition to thesustained release material of the matrix may control the release of thebutorphanol or pharmaceutically acceptable salt thereof from theformulation, such that blood levels of active ingredient are maintainedwithin the therapeutic range over an extended period of time. In certainalternate embodiments, the matrix is encapsulated.

In certain preferred embodiments, the sustained release oral dosage formof the present invention comprises a plurality of pharmaceuticallyacceptable sustained release matrices comprising butorphanol, the dosageform maintaining the blood plasma levels of butorphanol within thetherapeutic range over an extended period of time when administered topatients.

In some preferred embodiments, the dosage form of the inventioncomprises oral butorphanol formulated to release the butorphanol fromthe dosage form or to initiate the release of the butorphanol from thedosage form after a certain specific amount of time post-oral ingestion,or at an approximately specific anatomic location in thegastrointestinal tract, or when the dosage form is in contact withspecific gastrointestinal conditions (e.g., pH range, osmolarity,electrolyte content, food content, pressure, time since first ingestion,osmotic pressure in the dosage form, osmotic pressure in thegastrointestinal tract, hydration, etc), said dosage form suitable forproviding an orally effective therapeutic for a short, intermediate orextended duration of effect, said dosage form providing a rapid ordelayed onset of clinical effect.

In certain preferred embodiments the sustained release oral dosage formof the present invention is an osmotic dosage form which comprises asingle layer or bilayer core comprising butorphanol; an expandablepolymer; a semipermeable membrane surrounding the core; and a passagewaydisposed in the semipermeable membrane for sustained release of thebutorphanol or pharmaceutically acceptable salt thereof, such that bloodlevels of active ingredient are maintained within the therapeutic rangeover an extended period of time when administered to patients.

Other oral osmotic delivery systems may be used for the oraladministration of butorphanol.

In some preferred embodiments of the invention, the oral butorphanol isinterdispersed and are not isolated from each other in two distinctlayers.

In some preferred embodiments of the invention, the oral butorphanol isin the form of multiparticulates.

In some preferred embodiments of the invention, the oral butorphanol isdispersed in a matrix

In some preferred embodiments of the invention, the oral butorphanol isin the form of multiparticulates can be dispersed in a matrix orcontained in a capsule.

In some preferred embodiments of the invention, the oral butorphanol isin the form of multiparticulates can be dispersed in a matrix andcompressed into a tablet.

In some preferred embodiments of the invention, the oral butorphanol isin a matrix that is in the form of pellets.

In some preferred embodiments of the invention, the oral butorphanol isin coated beads.

In some preferred embodiments, the dosage form of the inventioncomprises a compressed tablet, compressed capsule or uncompressedcapsule. In other embodiments, the dosage form comprises a liquid fillcapsule.

In some preferred embodiments, the oral dosage in immediate or sustainedrelease form provides therapeutic effects that persist despite the lowor undectable butorphanol concentrations.

In some preferred embodiments, the dosage form of the inventioncomprises an oral formulation (e.g., tablet or capsule) which is coatedto prevent substantial direct contact of butorphanol with oral cavity(e.g. tongue, oral mucosa), oropharyngeal mucosal surface, esophagus orstomach.

In some preferred embodiments, the dosage form of the inventioncomprises an oral formulation which is coated with a film or polymer. Insome preferred embodiments, the dosage form of the invention comprisesbutorphanol in an enteric coating.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; said therapeutically effective amount in a reservoircomprising: (i) butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof; (ii) a membrane layer, said membranebeing substantially permeable to butorphanol; wherein the dosage formsubstantially releases the butorphanol from the dosage form to rendersaid dosage form suitable for extended release to a human patient.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a plurality of pharmaceuticallyacceptable beads coated with a therapeutically effective amount ofbutorphanol or a pharmaceutically acceptable salt of butorphanol, or amixture thereof; and overcoated with controlled release material torender said dosage form suitable for extended release oraladministration to a human patient.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising (i) a drug layer comprising atherapeutically effective amount of butorphanol; and (ii) a displacementlayer comprising an osmopolymer; and (b) a semipermeable wallsurrounding the bilayer core having a passageway disposed therein forthe release of said butorphanol or a pharmaceutically acceptable saltthereof; said dosage form suitable for extended release oraladministration to a human patient.

In some preferred embodiments, the oral dosage form is a controlledrelease material suitable for extended release in a human patient of thedosage form comprises a matrix. In some preferred embodiments, the saidmatrix is a plurality of multiparticulate matrices. In some preferredembodiments, the multiparticulates are compressed into a tablet. In somepreferred embodiments, the multiparticulates are disposed in apharmaceutically acceptable capsule.

In some preferred embodiments, the controlled release material of theoral dosage form of the invention is selected from the group consistingof hydrophobic polymers, hydrophilic polymers, gums, protein derivedmaterials, waxes, shellac, oils, fats and mixtures thereof.

In some preferred embodiments, the controlled release material of theoral dosage form of the invention is selected from the group consistingof polyethylene oxide, polyvinyl alcohol, hydroxypropyl methylcellulose, a carbomer and mixtures thereof.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol, ora mixture thereof; and material which imparts abuse deterrence, abuseresistance, tamper resistance, tamper deterrence qualities or whichotherwise deters the abuse, misuse, diversion or recreational use orabuse of the drug.

In some preferred embodiments, the controlled release material of theoral dosage form of the invention is selected from the group consistingof hydrogenated Type I or Type II vegetable oils, polyoxyethylenestearates and distearates, glycerol monostearate, and non-polymeric,non-water soluble liquids carbohydrate-based substances or poorly watersoluble, high melting point (mp=40 to 100° C.) waxes and mixturesthereof.

In some preferred embodiments, the oral dosage form comprises aplurality of pharmaceutically acceptable beads coated with drug andovercoated with controlled release material.

In some preferred embodiments, the oral dosage form comprises (i) a druglayer; and (ii) a displacement layer comprising an osmopolymer; and (b)a semipermeable wall surrounding the bilayer core having a passagewaydisposed therein for the release of said drug.

In some preferred embodiments, the oral dosage form comprises acompressed tablet, compressed capsule or uncompressed capsule. In somepreferred embodiments, the oral dosage form comprises a liquid fillcapsule.

In some preferred embodiments, the in vivo pharmacokinetic parameters ofthe specifications, embodiments and claims are derived or determinedunder fed conditions. In other preferred embodiments, the in vivopharmacokinetic parameters are derived or determined under fastedconditions.

In some preferred embodiments, the present invention excludes immediaterelease dosage forms.

In some preferred embodiments, the present invention excludes dosageforms devoid of controlled release material to render the dosage form asmodified release, delayed release, extended release or controlledrelease.

In some preferred embodiments, the present invention excludes dosageforms devoid of material to render the dosage form as modified release.

In some embodiments of the invention, the oral dosage form of theinvention exclude oral immediate release forms of butorphanol. In someembodiments of the invention, the oral dosage form of the inventionexcludes oral immediate release dosage forms of butorphanol which havebeen modified to enhance the solubility or bioavailability of thebutorphanol in the upper GI tract (e.g., by use of certain excipients orby physical manipulation of the butorphanol or granulation), usingmethods well know in the art, including complexation (e.g., withcyclodextrins), or particle size reduction (e.g., micronization), orlipid suspensions, solutions, emulsions, microemulsions, or mixedmicelles, or self-emulsifying drug delivery systems (SEDDS), orself-microemulsifying drug delivery systems (SMEDDS), or thixotropicvehicles, or surfactants, or solid dispersions, or liposomes, orco-solvents, or solvation.

In some embodiments of the invention, the oral dosage form of theinvention excludes oral dosage forms of butorphanol which have beenmodified to enhance the bioavailability of the butorphanol in the upperGI tract.

In some embodiments of the invention, the oral dosage forms ofbutorphanol are limited to controlled release butorphanol. In someembodiments of the invention, the oral dosage forms of butorphanol arelimited to controlled release butorphanol which are matrix or monolithicmatrix formulations. In some embodiments of the invention, the oraldosage forms of butorphanol exclude osmotic delivery dosage forms. Insome embodiments of the invention, the oral dosage forms of butorphanolexclude osmotic delivery dosage forms which are push-pull osmotic pumps(PPOP). In some embodiments of the invention, the oral dosage forms ofbutorphanol exclude osmotic delivery dosage forms which are controlledporosity osmotic pumps. In some embodiments of the invention, the oraldosage forms of butorphanol exclude multiparticulate matrix controlledrelease butorphanol formulations.

In some embodiments of the invention, the oral dosage forms ofbutorphanol are limited to controlled release butorphanol which providefirst release or first therapeutically beneficial release of butorphanolnot until about 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8hours after first oral ingestion, preferably at least about 2, 2.5, 3,3.5, or 4 hours after first oral ingestion. In some embodiments of theinvention, the oral dosage forms of butorphanol are limited tocontrolled release butorphanol which are overcoated with a pH sensitivematerial which dissolve at a pH<4, or pH<4.5, or pH, <5, or pH<5.5, orpH<6, or pH<6.5, or pH<6.8, or pH<7, or pH<7.2.

In some embodiments of the invention, the oral dosage form of theinvention excludes oral controlled release dosage forms of butorphanolwhich have been modified to enhance the solubility or bioavailability ofthe butorphanol in the upper GI tract through complexation (e.g., withcyclodextrins), or particle size reduction (e.g., micronization), orlipid suspensions, solutions, emulsions, microemulsions, mixed micelles,or self-emulsifying drug delivery systems (SEDDS), orself-microemulsifying drug delivery systems (SMEDDS), or thixotropicvehicles, or surfactants, or solid dispersions, or liposomes, orco-solvents, or solvation. In some embodiments of the invention, theoral dosage forms of butorphanol are limited to modified releasebutorphanol which provides an onset of therapeutic effect not beforeabout 1, 1, 5, 2, 2.5 3, 3.5, 4, 4.5, 5, 5.5 or 6 hours following firstingestion.

In some embodiments of the invention, the oral dosage forms ofbutorphanol are limited to modified release butorphanol which providesquantifiable or therapeutic or substantial plasma concentrations notbefore about 1, 1, 5, 2, 2.5 3, 3.5, 4, 4.5, 5, 5.5 or 6 hours followingfirst ingestion. In some embodiments of the invention, the oral dosageforms of butorphanol are limited to modified release butorphanol whichprovide quantifiable, or substantial plasma concentrations ortherapeutic plasma concentrations not before about 1, 1, 5, 2, 2.5 3,3.5, 4, 4.5, 5, 5.5 or 6 hours following first ingestion. In someembodiments of the invention, the oral dosage forms of butorphanol arelimited to modified release butorphanol which are osmotic deliverydosage forms (e.g., push pull osmotic pumps, monolithic osmotic deliverysystems and controlled porosity osmotic pumps).

In some embodiments of the invention, the oral dosage forms ofbutorphanol are limited to modified release butorphanol which areosmotic delivery dosage forms, overcoated with a pH sensitive materialwhich dissolve at a pH<4, or pH<4.5, or pH, <5, or pH<5.5, or pH<6, orpH<6.5, or pH<6.8, or pH<7, or pH<7.2. In some embodiments of theinvention, the oral dosage forms of butorphanol are limited to modifiedrelease butorphanol which provide release of all, substantially all, ormost of the butorphanol only at pH>4, or pH>4.5, or pH, >5, or pH>5.5,or pH>6, or pH>6.5, or pH>7, or pH>7.5, or pH>7.8 upon dissolution usingthe USP Paddle Method for 2 hours at 37° C. at 100 rpm in 900 mLdistilled water adjusted for pH.

In some embodiments of the invention, the oral dosage forms ofbutorphanol are limited to modified release butorphanol which providerelease of all, substantially all, or most of the butorphanol distal tothe stomach, distal to the duodenum, distal to the jejunum, distal tothe ileum, or distal to the ileo-cecal junction. In some embodiments ofthe invention, the oral dosage forms of butorphanol are limited tomodified release butorphanol which provide release of all, substantiallyall, or most of the butorphanol at least about 1, 1.5, 2, 2.5, 3, 3.5,4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion,preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oralingestion. In some embodiments of the invention, the oral dosage formsof butorphanol are limited to modified release butorphanol which beginthe release of all, substantially all, most, or some of the butorphanolat least about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5,or 8 hours after first oral ingestion, preferably at least about 2, 2.5,3, 3.5, or 4 hours after first oral ingestion.

In some embodiments of the invention, the oral dosage forms ofbutorphanol are limited to modified release butorphanol which providethe intended therapeutic effect not until about 1, 1.5, 2, 2.5, 3, 3.5,4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion,preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oralingestion. In some embodiments of the invention, the oral dosage formsof butorphanol are limited to modified release butorphanol which provideall, substantially all, most, or some of the intended therapeutic effectnot until about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5,or 8 hours after first oral ingestion, preferably at least about 2, 2.5,3, 3.5, or 4 hours after first oral ingestion. In some embodiments ofthe invention, the oral dosage forms of butorphanol are limited tomodified release butorphanol which begin to provide all, substantiallyall, most, or some of the intended therapeutic effect not until about 1,1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours afterfirst oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or 4hours after first oral ingestion.

In some embodiments of the invention, the oral dosage forms ofbutorphanol are limited to modified release butorphanol which provide apsychic effect in recreational drug or opioid users and drug or opioidabusers not until about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5,7, 7.5, or 8 hours after first oral ingestion, preferably at least about2, 2.5, 3, 3.5, or 4 hours after first oral ingestion. In someembodiments of the invention, the oral dosage forms of butorphanol arelimited to modified release butorphanol provide a psychic effect inrecreational drug or opioid users and drug or opioid abusers not untilabout 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hoursafter first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or4 hours after first oral ingestion. In some embodiments of theinvention, the oral dosage forms of butorphanol are limited to modifiedrelease butorphanol which begin to provide a psychic effect inrecreational drug or opioid users and drug or opioid abusers not untilabout 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hoursafter first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or4 hours after first oral ingestion.

In some embodiments of the invention, the oral dosage forms ofbutorphanol are limited to modified release butorphanol which result inlittle or no nausea, or little or no sedation until about 1, 1.5, 2,2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oralingestion, preferably at least about 2, 2.5, 3, 3.5, or 4 hours afterfirst oral ingestion. In some embodiments of the invention, the oraldosage forms of butorphanol are limited to modified release butorphanolwhich result in little or no nausea, or little or no sedation untilabout 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hoursafter first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or4 hours after first oral ingestion. In some embodiments of theinvention, the oral dosage forms of butorphanol are limited to modifiedrelease butorphanol which result in little or no nausea, or little or nosedation until about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7,7.5, or 8 hours after first oral ingestion, preferably at least about 2,2.5, 3, 3.5, or 4 hours after first oral ingestion.

In some embodiments of the invention, the oral dosage forms ofbutorphanol are limited to modified release butorphanol which provideall, substantially all, most, or some of the release of butorphanol fromthe dosage form distal to the stomach, or distal to the duodenum, ordistal to the jejunum, or distal to the ileum, or distal to theileo-cecal junction, or in the colon.

In some embodiments of the invention, the oral dosage forms ofbutorphanol are limited to butorphanol without an additional therapeuticagent (e.g., acetaminophen, COX-2 inhibitor, NSAID, methadone)incorporated in the dosage form or given concurrently with the dosageform of the invention. In some embodiments of the invention, the oraldosage forms of butorphanol are limited to butorphanol without anadditional therapeutic agent to treat the same medical condition or toenhance the effect of the butorphanol which is incorporated in thedosage form or given concurrently with the dosage form of the invention.

In some embodiments, the invention excludes oral butorphanolpharmaceutical compositions which provide a more rapid onset of actionof butorphanol compared with intranasal butorphanol, orally ingestedbutorphanol active pharmaceutical ingredient (API), oral immediaterelease butorphanol.

In some embodiments, the invention excludes oral butorphanolpharmaceutical compositions for the treatment of acute pain. In someembodiments, the invention excludes oral butorphanol pharmaceuticalcompositions for the treatment of addiction disorders. In someembodiments, the invention is limited to oral butorphanol pharmaceuticalcompositions for the treatment of chronic pain.

In some embodiments of the invention, the invention excludes oralbutorphanol pharmaceutical compositions which provide more rapid (or“improved”) dissolution of the butorphanol when oral immediate releasebutorphanol made using conventional excipients. In some embodiments, theinvention excludes oral butorphanol pharmaceutical compositions whichprovide greater than 65%, or greater than 75%, or greater than 85%release of butorphanol form the dosage form when measured by USP PaddleMethod at 50 or 100 rpm in 900 mL of 0.1 N HCl buffer (at any pH between1.6 and 3) at 37° C. after 45 minutes. In some embodiments, theinvention excludes oral butorphanol pharmaceutical compositions whichprovide greater than about 50%, or about 60% or about 70%, or about 80%release of butorphanol form the dosage form when measured by USP PaddleMethod at 50 or 100 rpm in 900 mL of pH 6.8 buffer at 37° C. after 60minutes.

Some or all of the objects and others are achieved by embodiments of thepresent invention, which is directed in part to a dosage form of oralbutorphanol in modified release dosage form.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for the treatment ofpain.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for the treatment ofchronic pain.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for the treatment ofneuropathic pain.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for the treatment ofcancer pain.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for the treatment ofpain, excluding acute pain.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for the treatment ofpain, excluding acute postsurgical pain.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for the treatment ofpain which is unresponsive to other oral formulations of opioidanalgesics, particularly full or pure mu opioid agonists.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for the treatment ofpain which is unresponsive to other oral formulations of pure or fullmu-opioid receptor agonists.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended for the treatment of painwhich is unresponsive to intranasal butorphanol.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for the treatment ofpain in patients with an addiction disorder or at significant risk of anaddiction disorder.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for the treatment ofaddiction disorders.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for the treatment ofopioid addiction disorders.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for the treatment ofaddiction disorders unresponsive to methadone.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for treatmentunresponsive to intranasal butorphanol.

In some preferred embodiments, the dosage form provides an oral extendedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol or a mixture thereof; said dosage form intended solely fortreatment unresponsive to oral immediate release butorphanol.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; said dosage form intended solely for the treatment ofpruritus, or cough, or fibromylagia, or restless leg syndrome or urinaryincontinence, or a condition other than pain.

The invention is also directed to kits of the dosage forms, includingkits for titration disclosed herein.

In another aspect, the invention relates to a method for prevention ortreatment of pain, cough, dyspnea, opioid addiction disorders, restlessleg syndrome, acute herpes zoster, visceral pain, breakthrough pain,opioid dependence and urinary incontinence, comprising oraladministration of a dosage form containing butorphanol or apharmaceutically acceptable salt of butorphanol or a mixture thereof.

In another aspect, the invention relates to a method for prevention ortreatment of butorphanol responsive or opioid responsive medicalconditions, comprising oral administration of a dosage form containingbutorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; an oral controlled release material to render saiddosage form suitable for extended release, or delayed onset, extendedrelease or delayed onset, rapid release or delayed onset, pulsatilerelease in a human patient; said dosage form administered at aprespecified dosing regimen; said dosing regimen associated with reducedside effects, improved tolerability, improved efficiency of therapeuticresponse, reduced breakthrough symptoms (e.g., breakthrough pain) andreduced treatment discontinuation due to side effects.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; optionally, an oral controlled release material torender said dosage form suitable for extended release, or delayed onset,extended release or delayed onset, rapid release or delayed onset,pulsatile release in a human patient; said dosage form administered at aprespecified dosing regimen; said dosing regimen associated with reducedside effects, improved tolerability, improved efficiency of therapeuticresponse, reduced breakthrough symptoms (e.g., breakthrough pain) andreduced treatment discontinuation due to side effects.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; said dosage form suitable oral immediate release in ahuman patient; said dosage form administered at a prespecified dosingregimen; said dosing regimen associated with reduced side effects,improved tolerability, improved efficiency of therapeutic response,reduced breakthrough symptoms (e.g., breakthrough pain) and reducedtreatment discontinuation due to side effects.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; optionally; said dosage form intended to treat pediatricpatients; said dosage form administered at a prespecified dosingregimen; said dosing regimen as provided herein, except that the dose ortotal daily dose (as applicable) is multiplied by the ratio obtainedfrom the child's weight in kilograms divided by 70 kilograms.

As used herein, “plasma T_(lag)” refers to a time period from firstadministration (or first dosing) of butorphanol to the occurrence offirst of two consecutive plasma butorphanol concentrations of not lessthan 0.75 ng/mL per mg of administered butorphanol base, provided thatthe second consecutive butorphanol plasma concentration is obtained notless than 10 minutes and not more than 20 minutes after the first plasmabutorphanol concentration.

In some embodiments, the plasma T_(lag) of the oral butorphanol dosageform is more than about 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25,2.5, 2.75, 3, 3.5, 4, 4.5, or 5 hours. Preferably, the T_(lag) is atleast 1 hour, more preferably, at least 1.5 hours and most preferably atleast 2 to 4 hours.

As used herein, “T_(lag(x))” refers to the time from the start ofdissolution testing to the first attainment of an in-vitro release ofabout 5% by weight of the active drug from the dosage form rate whenmeasured by the USP Basket or Paddle Method at 100 rpm in 900 mL ofdissolution media at 37° C., where “_((x))” is the pH of the dissolutionmedia.

In some embodiments, the T_(lag(5.0)), T_(lag(5.5)), T_(lag(6.8))T_(lag(7.0)), and T_(lag(7.2)) of the oral butorphanol dosage form ismore than about 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75,3, 3.5, 4 or 5 hours, preferably more than about 2, 2.25, 2.5, 2.75, or3 hours.

In some embodiments, where the oral dosage form of the inventionincorporates controlled release material, the T_(lag(5.0)),T_(lag(5.5)), T_(lag(6.8)) T_(lag(7.0)), and T_(lag(7.2)) of the oralbutorphanol dosage form is more than about 0.25, 0.5, 0.75, 1, 1.25,1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, or 4 hours, preferably more thanabout 2, 2.25, 2.5, 2.75, or 3 hours.

In some embodiments, where the oral dosage form of the inventionincorporates controlled release material, the T_(lag(7.2)) of the oralbutorphanol dosage form is more than about 0.25, 0.5, 0.75, 1, 1.25,1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, or 4 hours, preferably more thanabout 2, 2.25, 2.5, 2.75, or 3 hours.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and controlled release material to render said dosageform suitable for delayed onset, rapid release or delayed onset,pulsatile release, said dosage form releasing or delivering butorphanolat a rate of about 0.05 mg/hr, or 0.1 mg/hr, or 0.2 mg/hr, or 0.3 mg/hr,or 0.4 mg/hr, or 0.5 mg/hr, or 0.6 mg/hr, or 0.7 mg/hr, or 0.8 mg/hr, or0.9 mg/hr, or 1 mg/hr, or 1.1 mg/hr, or 1.2 mg/hr, or 1.3 mg/hr, or 1.4mg/hr, or 1.5 mg/hr, or 1.6 mg/hr, or 1.7 mg/hr, or 1.8 mg/hr, or 2mg/hr, or 2.2 mg/hr, or 2.3 mg/hr, or 2.4 mg/hr, or 2.5 mg/hr, or 2.6mg/hr, or 2.7 mg/hr, or 2.8 mg/hr, or 2.9 mg/hr, or 3 mg/hr, or 3.4mg/hr, or 3.5 mg/hr, or 3.6 mg/hr, or 3.7 mg/hr, or 3.8 mg/hr, or 3.9mg/hr, or 4 mg/hr, or 4.2 mg/hr, or 4.4 mg/hr, or 4.6 mg/hr, or 4.8mg/hr, or 5 mg/hr, or 5.5 mg/hr, or 6 mg/hr, or 6.5 mg/hr, or 7 mg/hr,or 7.5 mg/hr, or 8 mg/hr, or 8.5 mg/hr, or 9 mg/hr, or 9.5 mg/hr, or 10mg/hr, or 11 mg/hr, or 12 mg/hr, or 14 mg/hr, or 16 mg/hr, or 18 mg/hr,or 20 mg/hr, or 25 mg/hr, or 30 mg/hr, or 35 mg/hr, or 40 mg/hr, or 50mg/hr.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and controlled release material to render said dosageform suitable for controlled release or delayed onset, extended release,said dosage form releasing or delivering butorphanol at a controlledrate of release of about 0.1 mg/hr, or 0.2 mg/hr, or 0.3 mg/hr, or 0.4mg/hr, or 0.5 mg/hr, or 0.6 mg/hr, or 0.7 mg/hr, or 0.8 mg/hr, or 0.9mg/hr, or 1 mg/hr, or 1.1 mg/hr, or 1.2 mg/hr, or 1.3 mg/hr, or 1.4mg/hr, or 1.5 mg/hr, or 1.6 mg/hr, or 1.7 mg/hr, or 1.8 mg/hr, or 2mg/hr, or 2.2 mg/hr, or 2.3 mg/hr, or 2.4 mg/hr, or 2.5 mg/hr, or 2.6mg/hr, or 2.7 mg/hr, or 2.8 mg/hr, or 2.9 mg/hr, or 3 mg/hr, or 3.4mg/hr, or 3.5 mg/hr, or 3.6 mg/hr, or 3.7 mg/hr, or 3.8 mg/hr, or 3.9mg/hr, or 4 mg/hr, or 4.2 mg/hr, or 4.4 mg/hr, or 4.6 mg/hr, or 4.8mg/hr, or 5 mg/hr, or 6 mg/hr, or 7 mg/hr, or 8 mg/hr, or 9 mg/hr, or 10mg/hr, more preferably at a rate of about 0.2 mg/hr, or 0.3 mg/hr, or0.4 mg/hr, or 0.5 mg/hr, or 0.6 mg/hr, or 0.7 mg/hr, or 0.8 mg/hr, or0.9 mg/hr, or 1 mg/hr, or 1.1 mg/hr, or 1.2 mg/hr, or 1.3 mg/hr, or 1.4mg/hr, or 1.5 mg/hr, or 1.6 mg/hr, or 1.7 mg/hr, or 1.8 mg/hr, or 2mg/hr, or 2.2 mg/hr, or 2.3 mg/hr, or 2.4 mg/hr, or 2.5 mg/hr, or 2.6mg/hr, or 2.7 mg/hr, or 2.8 mg/hr, or 2.9 mg/hr, or 3 mg/hr, or 3.4mg/hr, or 3.5 mg/hr, or 3.6 mg/hr, or 3.7 mg/hr, or 3.8 mg/hr, or 3.9mg/hr, or 4 mg/hr, or 4.2 mg/hr, or 4.4 mg/hr, or 4.6 mg/hr, or 4.8mg/hr, or 5 mg/hr, or 5.5 mg/hr, or 6 mg/hr, or 6.5 mg/hr, or 7 mg/hr,or 7.5 mg/hr, or 8 mg/hr.

In some preferred embodiments where the oral butorphanol dosage formincorporates a controlled release material to render said dosage formsuitable for controlled release or delayed onset, extended release in ahuman patient, said dosage form releases or delivers butorphanol at acontrolled rate of release of 0.2 mg/hr to 8 mg/hr, more preferably 0.4mg/hr to 6 mg/hr, or 0.4 mg/hr to 4 mg/hr.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol, said dosage form a modified release form, said dosageform releasing or delivering butorphanol at a controlled rate of releaseof about 0.1 mg/hr to about 8 mg/hr, or about 0.2 mg/hr to about 8mg/hr, or about 0.3 mg/hr to about 8 mg/hr, or about 0.4 mg/hr to about8 mg/hr, or 0.5 mg/hr to about 8 mg/hr, or 0.6 mg/hr to about 8 mg/hr,or about 0.7 mg/hr to about 8 mg/hr, or about 0.8 mg/hr to about 8mg/hr, or about 0.9 mg/hr to about 8 mg/hr, or about 1 mg/hr to about 8mg/hr, or about 0.4 mg/hr to about 7 mg/hr, or about 0.4 mg/hr to about6 mg/hr, or 0.4 mg/hr to about 5 mg/hr, or 0.4 mg/hr to about 3 mg/hr,or about 0.4 mg/hr to about 3 mg/hr, or about 0.2 mg/hr to about 5mg/hr.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and controlled release material to render said dosageform suitable for controlled release or delayed onset, extended releasein a human patient, said dosage form releasing or delivering butorphanolat a controlled rate of release of about 0.1 mg/hr to about 4 mg/hr, orabout 0.2 mg/hr to about 4 mg/hr, or about 0.3 mg/hr to about 4 mg/hr,or about 0.4 mg/hr to about 4 mg/hr, or 0.5 mg/hr to about 4 mg/hr, or0.6 mg/hr to about 4 mg/hr, or about 0.7 mg/hr to about 4 mg/hr, orabout 0.8 mg/hr to about 4 mg/hr, or about 0.9 mg/hr to about 4 mg/hr,or about 1 mg/hr to about 4 mg/hr, or about 1.2 mg/hr to about 4 mg/hr,or about 1.4 mg/hr to about 4 mg/hr, or 1.5 mg/hr to about 4 mg/hr, or1.6 mg/hr to about 4 mg/hr, or about 1.8 mg/hr to about 4 mg/hr, orabout 2 mg/hr to about 4 mg/hr.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and controlled release material to render said dosageform suitable for controlled release or delayed onset, extended releasein a human patient, said dosage form releasing or delivering butorphanolat a controlled rate of release of about 0.1 mg/hr to about 3 mg/hr, orabout 0.2 mg/hr to about 3 mg/hr, or about 0.3 mg/hr to about 3 mg/hr,or about 0.4 mg/hr to about 3 mg/hr, or 0.5 mg/hr to about 3 mg/hr, or0.6 mg/hr to about 3 mg/hr, or about 0.7 mg/hr to about 3 mg/hr, orabout 0.8 mg/hr to about 3 mg/hr, or about 0.9 mg/hr to about 3 mg/hr,or about 1 mg/hr to about 3 mg/hr, or about 1.2 mg/hr to about 3 mg/hr,or about 1.4 mg/hr to about 3 mg/hr, or 1.5 mg/hr to about 3 mg/hr, or1.6 mg/hr to about 3 mg/hr, or about 1.8 mg/hr to about 3 mg/hr, orabout 2 mg/hr to about 3 mg/hr.

In some preferred embodiments where the oral butorphanol dosage formincorporates a controlled release material to render it controlledrelease or delayed onset suitable for dosing every 6 hours, said dosageform releases or delivers butorphanol at a controlled rate of releasefor a period of about 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours.

In some preferred embodiments where the oral butorphanol dosage formincorporates a controlled release material to render it controlledrelease or delayed onset suitable for dosing every 8 hours, said dosageform releases or delivers butorphanol at a controlled rate of releasefor a period of about 4, 5, 6, 7, 8, 9, 10 or 12 hours.

In some preferred embodiments where the oral butorphanol dosage formincorporates a controlled release material to render it controlledrelease or delayed onset suitable for dosing every 12 hours, said dosageform releases or delivers butorphanol at a controlled rate of releasefor a period of about 7, 8, 9, 10, 11, 12, 14, 16 or 18 hours.

In some preferred embodiments where the oral butorphanol dosage formincorporates a controlled release material to render it controlledrelease or delayed onset suitable for dosing every 24 hours, said dosageform releases or delivers butorphanol at a controlled rate of releasefor a period of about 12, 14, 16, 18, 20, 22, 24, 26 or 30 hours.

In some preferred embodiments where the oral butorphanol dosage formincorporates a controlled release material to render it delayed onset(e.g., release or delivery of drug distal to the stomach, duodenum, orileum) and where said delayed onset dosage form is intended to providerapid release or burst release upon reaching the target GI anatomiclocation or GI environment, or at a desired time after oral ingestion(e.g., 2 to 6 hours), the dosage form releases or delivers butorphanolin less than about 15, 30, 60, 90, 120, 160, 180 or 240 minutes,preferably in less than about 15, 30, 60, 90, or 120 minutes.

As used herein, “controlled rate of release” refers to the release ordelivery of the active drug from the oral dosage form of the inventionat rate per unit time over an extended period of time, or any timeperiod over thirty-minutes up to thirty hours.

In some more preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; an oral controlled release material to render saiddosage form extended release and suitable for duodenal, jejunal or ilealdelivery or release; said dosage form administered at a prespecifieddosing regimen; said regimen comprising administering a dose of about 5mg to about 10 mg for about 1 to about 16 days, then about 15 mg toabout 80 mg for at least 1 day and optionally thereafter; or a dose ofabout 10 mg to about 20 mg for about 1 to about 16 days, then about 21mg to about 80 mg for at least 1 day and optionally thereafter. In someembodiments, the foregoing doses and dose ranges of said prespecifieddosing regimens are the total daily dose (e.g., “about 5 mg to about 10mg for about 3 to about 10 days” is a total daily dose of about 5 mg toabout 10 mg taken for about 3 to about 10 days). In some otherembodiments, the foregoing doses and dose ranges of said prespecifieddosing regimens are the doses (or unit doses) at individual drugadministration times (e.g., “about 5 mg to about 10 mg for about 1 toabout 16 days” is about 5 mg to about 10 mg at each dosing time [e.g.,Q8H, or Q12H or Q24H], taken for about 1 to about 16 days). In otherembodiments, the foregoing doses and dose ranges of said prespecifieddosing regimens are the daily dose (e.g., “about 5 mg to about 10 mg forabout 1 to about 16 days” is about 5 mg to about 10 mg total daily dose,taken for about 1 to about 16 days).

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; optionally; said dosage form intended to treat pediatricpatients; said dosage form administered at a prespecified dosingregimen; said dosing regimen providing a mean butorphanol area under theplasma concentration time curve (AUC) as provided herein, except thatthe AUC is multiplied by the ratio obtained from the child's weight inkilograms divided by 70 kilograms.

In some more preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; an oral controlled release material to render saiddosage form extended release and suitable for duodenal, jejunal or ilealdelivery or release; said regimen comprising administering a dose whichprovides a mean butorphanol area under the plasma concentration timecurve to 24 hours post-dose (AUC₀₋₂₄) of about 1 ng·hr/mL to about 27ng·hr/mL for about for about 1 to about 16 days, then about then about 3ng·hr/mL to about 214 ng·hr/mL for at least 1 day and optionallythereafter; or a dose of about then about 2 ng·hr/mL to about 4 ng·hr/mLfor about 1 to about 16 days, then about then about 2.1 ng·hr/mL toabout 214 ng·hr/mL for at least 1 day and optionally thereafter. In someembodiments, the foregoing mean butorphanol area under the plasmaconcentration time curve is calculated from time of administration toinfinity (AUC_(0-inf)). In other embodiments, the foregoing meanbutorphanol area under the plasma concentration time curve is calculatedfrom time of administration to 24 hours (AUC₀₋₂₄).

In some more preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; an oral controlled release material to render saiddosage form extended release and suitable for duodenal, jejunal or ilealdelivery or release; said regimen comprising administering a total dailydose which provides a mean butorphanol area under the plasmaconcentration time curve to 24 hours post-dose (AUC₀₋₂₄) of about 1ng·hr/mL to about 27 ng·hr/mL for about for about 1 to about 16 days,then about then about 3 ng·hr/mL to about 214 ng·hr/mL for at least 1day and optionally thereafter; or a dose of about then about 2 ng·hr/mLto about 4 ng·hr/mL for about 1 to about 16 days, then about then about2.1 ng·hr/mL to about 214 ng·hr/mL for at least 1 day and optionallythereafter. In some embodiments, the foregoing mean butorphanol areaunder the plasma concentration time curve is calculated from time ofadministration to infinity (AUC_(0-inf)). In other embodiments, theforegoing mean butorphanol area under the plasma concentration timecurve is calculated from time of administration to 24 hours (AUC₀₋₂₄).

In some more preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; an oral controlled release material to render saiddosage form extended release and suitable for duodenal, jejunal or ilealdelivery or release; said regimen comprising administering a dose whichprovides a mean peak plasma concentration of about 0.1 ng/mL to about0.2 ng·hr/mL for about for about 1 to about 16 days, then about thenabout 0.3 ng·hr/mL to about 8 ng·hr/mL for at least 1 day and optionallythereafter; or a dose of about then about 0.2 ng·hr/mL to about 0.44ng·hr/mL for about 1 to about 16 days, then about then about 0.21ng·hr/mL to about 8 ng·hr/mL for at least 1 day and optionallythereafter.

In a preferred embodiment, the dosage form containing butorphanol or apharmaceutically acceptable salt of butorphanol or a mixture thereof isan extended release form. Oral, extended release butorphanol has severaldistinct advantages over oral immediate release opioids and overintranasal opioids, including fewer interruptions in sleep, reduceddependence on caregivers, improved compliance, enhanced quality of lifeoutcomes, and increased control over the management of their malady(e.g., pain). In addition, such formulations can provide more constantplasma concentrations and clinical effects, less frequent peak to troughfluctuations and fewer side effects.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof; optionally, a controlled release material to rendersaid dosage form suitable for up to every 24 hour (once-a-day)administration to a human patient; said dosage form providing at least10% of the steady state concentration of butorphanol afteradministration of one dose at its intended dosing frequency. In otherpreferred embodiments, the dosage form provides at least about 15%, orat least about 20%, or at least about 30%, or at least about 40%, or atleast about 50%, or at least about 60%, or at least about 70%, or atleast about 75%, or at least about 80%, or at least about 85%, or atleast about 90% of the steady state therapeutic concentration ofbutorphanol after administration of one dose or two doses at theirintended dosing frequency.

In some preferred embodiments, the invention provides a method ofproviding relief in a human patient suffering from pain comprising atherapeutically effective amount of oral butorphanol or apharmaceutically acceptable salt of butorphanol or a mixture thereof.

In some preferred embodiments, the invention provides a method ofproviding relief in a human patient suffering from cough, dyspnea,opioid addiction disorders, restless leg syndrome, fibromylagia,diarrhea, irritable bowel syndrome, pruritus, acute herpes zoster,visceral pain, breakthrough pain, opioid dependence and urinaryincontinence comprising a therapeutically effective amount of oralbutorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof.

In some preferred embodiments, the invention provides a method ofproviding relief in a human patient suffering from a butorphanolresponsive medical condition comprising a therapeutically effectiveamount of oral butorphanol or a pharmaceutically acceptable salt ofbutorphanol or a mixture thereof.

In some preferred embodiments, the oral pharmaceutical composition isused on a time contingent basis.

In some preferred embodiments, the oral pharmaceutical composition isused on a pain contingent basis.

In some preferred embodiments, the Q4H or Q4H PRN oral pharmaceuticalcomposition provides a therapeutic effect for about 4 hours.

In some preferred embodiments, the QID, Q6H or Q6H PRN oralpharmaceutical composition provides a therapeutic effect for about 6hours.

In some preferred embodiments, the TID, Q8H or Q8H PRN oralpharmaceutical composition provides a therapeutic effect for about 8hours.

In some preferred embodiments, the Q4H or Q4H PRN oral pharmaceuticalcomposition provides a C_(max) of butorphanol at about 1 to about 4hours.

In some preferred embodiments, the Q4H or Q4H PRN oral pharmaceuticalcomposition provides a C_(min) of butorphanol at about 3 to 6 hours.

In some preferred embodiments, the Q4H or Q4H PRN oral pharmaceuticalcomposition provides a mean butorphanol AUC_(0-inf) after firstadministration or AUC₀₋₄ at steady state of about 0.5 ng·hr/mL to about100 ng·hr/mL, or about 0.5 ng·hr/mL to about 75 ng·hr/mL or about 0.5ng·hr/mL to about 40 ng·hr/mL, or about 0.5 ng·hr/mL to about 30ng·hr/mL, or about 0.5 ng·hr/mL to about 20 ng·hr/mL or about 0.5ng·hr/mL to about 10 ng·hr/mL, about 0.5 ng·hr/mL to about 5 ng·hr/mL,or about 0.5 ng·hr/mL to about 3 ng·hr/mL or about 0.5 ng·hr/mL to about2 ng·hr/mL.

In some preferred embodiments, the Q4H or Q4H PRN oral pharmaceuticalcomposition provides a mean of butorphanol C₄/Cmax ratio of 0.05 toabout 1.25.

In some preferred embodiments, the Q4H or Q4H PRN oral pharmaceuticalcomposition provides a butorphanol percent fluctuation of less than400%.

In some preferred embodiments, the Q4H or Q4H PRN oral pharmaceuticalcomposition provides of butorphanol W₅₀ of 0.5 to about 3.5 hours.

In some preferred embodiments, the Q4H or Q4H PRN oral pharmaceuticalcomposition provides a HVD of butorphanol of 0.75 to about 3.75 hours.

In some preferred embodiments, the Q4H or Q4H PRN oral pharmaceuticalcomposition provides an AI of butorphanol of not more than 4.0.

In some preferred embodiments, the Q6H or Q6H PRN oral pharmaceuticalcomposition provides a C_(max) of butorphanol at about 1 to about 6hours.

In some preferred embodiments, the Q6H or Q6H PRN oral pharmaceuticalcomposition provides a C_(min) of butorphanol at about 3 to 8 hours.

In some preferred embodiments, the Q6H or Q6H PRN oral pharmaceuticalcomposition provides a mean butorphanol AUC_(0-inf) after firstadministration or AUC₀₋₆ at steady state of about 0.5 ng·hr/mL to about100 ng·hr/mL, or about 0.5 ng·hr/mL to about 75 ng·hr/mL or about 0.5ng·hr/mL to about 40 ng·hr/mL, or about 0.5 ng·hr/mL to about 30ng·hr/mL, or about 0.5 ng·hr/mL to about 20 ng·hr/mL or about 0.5ng·hr/mL to about 10 ng·hr/mL, about 0.5 ng·hr/mL to about 5 ng·hr/mL,or about 0.5 ng·hr/mL to about 3 ng·hr/mL or about 0.5 ng·hr/mL to about2 ng·hr/mL.

In some preferred embodiments, the Q6H or Q6H PRN oral pharmaceuticalcomposition provides a mean of butorphanol C₄/Cmax ratio of 0.05 toabout 1.25.

In some preferred embodiments, the Q6H or Q6H PRN oral pharmaceuticalcomposition provides a butorphanol percent fluctuation of less than400%.

In some preferred embodiments, the Q6H or Q6H PRN oral pharmaceuticalcomposition provides of butorphanol W₅₀ of 1.0 to about 5 hours.

In some preferred embodiments, the Q6H or Q6H PRN oral pharmaceuticalcomposition provides a HVD of butorphanol of 1.25 to about 5.5 hours.

In some preferred embodiments, the Q6H or Q6H PRN oral pharmaceuticalcomposition provides an AI of butorphanol of not more than 4.0.

In some preferred embodiments, the TID or Q8H oral pharmaceuticalcomposition provides a C_(max) of butorphanol at about 1 to about 6hours.

In some preferred embodiments, the TID or Q8H oral pharmaceuticalcomposition provides a C_(min) of butorphanol at about 6 to 10 hours.

In some preferred embodiments, the TID or Q8H oral pharmaceuticalcomposition provides a mean butorphanol AUC_(0-inf) after firstadministration or AUC₀₋₈ at steady state of about 0.5 ng·hr/mL to about200 ng·hr/mL, or about 0.5 ng·hr/mL to about 150 ng·hr/mL, or about 0.5ng·hr/mL to about 100 ng·hr/mL, or about 0.5 ng·hr/mL to about 75ng·hr/mL or about 0.5 ng·hr/mL to about 40 ng·hr/mL, or about 0.5ng·hr/mL to about 30 ng·hr/mL, or about 0.5 ng·hr/mL to about 20ng·hr/mL or about 0.5 ng·hr/mL to about 10 ng·hr/mL, about 0.5 ng·hr/mLto about 5 ng·hr/mL, or about 0.5 ng·hr/mL to about 3 ng·hr/mL or about0.5 ng·hr/mL to about 2 ng·hr/mL.

In some preferred embodiments, the TID or Q8H oral pharmaceuticalcomposition provides a mean of butorphanol C₈/Cmax ratio of 0.05 toabout 1.25.

In some preferred embodiments, the TID or Q8H oral pharmaceuticalcomposition provides a butorphanol percent fluctuation of less than400%.

In some preferred embodiments, the TID or Q8H oral pharmaceuticalcomposition provides of butorphanol W₅₀ of 1.5 to about 6.5 hours.

In some preferred embodiments, the TID or Q8H oral pharmaceuticalcomposition provides a HVD of butorphanol of 2 to about 7 hours.

In some preferred embodiments, the TID or Q8H oral pharmaceuticalcomposition provides an AI of butorphanol of not more than 4.0.

In some preferred embodiments, the invention comprises an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof; said dosage from providing a C_(max)of butorphanol from about 0.025 ng/mL to about 30 ng/mL. In otherpreferred embodiments, the dosage form provides a C_(max) of butorphanolof about 0.05 ng/mL to about 30 ng/mL, or about 0.75 ng/mL to about 30ng/mL, or about 0.1 ng/mL to about 30 ng/mL, or about 0.2 ng/mL to about30 ng/mL, or about 0.3 ng/mL to about 30 ng/mL, or about 0.4 ng/mL toabout 30 ng/mL, or about 0.05 ng/mL to about 25 ng/mL, or about 0.05ng/mL to about 20 ng/mL, or about 0.05 ng/mL to about 18 ng/mL, or about0.05 ng/mL to about 15 ng/mL, or about 0.05 ng/mL to about 12 ng/mL, orabout 0.05 ng/mL to about 10 ng/mL, or about 0.05 ng/mL to about 8ng/mL, or about 0.05 ng/mL to about 7 ng/mL, or about 0.05 ng/mL toabout 6 ng/mL, or about 0.05 ng/mL to about 5 ng/mL, or about 0.05 ng/mLto about 4 ng/mL, or about 0.05 ng/mL to about 3 ng/mL, or about 0.1ng/mL to about 7 ng/mL, or about 0.1 ng/mL to about 6 ng/mL, or about0.1 ng/mL to about 5 ng/mL, or about 0.1 ng/mL to about 4 ng/mL, orabout 0.1 ng/mL to about 3 ng/mL.

In some preferred embodiments, the invention comprises an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; said dosage from providing a C_(max) of butorphanoloccurring from a mean of about 0.25 to about 30 hours. In otherpreferred embodiments, the dosage form provides a C_(max) of butorphanoloccurring from a mean of about 0.5 to about 30 hours, or from a mean ofabout 1 to about 30 hours, or about 1 to about 26 hours, or about 1 toabout 24 hours, or about 1 to about 20 hours, or about 1 to about 18hours, or about 1 to about 16 hours, or about 1 to about 14 hours, orabout 1 to about 12 hours, or about 1 to about 10 hours, or about 1 toabout 8 hours, or about 1 to about 6 hours, or about 1 to about 4 hours,or about 1 to about 3 hours, or about 2 to about 30 hours, or about 4 toabout 30 hours, or about 4 to about 24 hours, or about 6 to about 24hours, or about 8 to about 24 hours, or about 10 to about 20 hours, orabout 12 to about 24 hours, or about 18 to about 24 hours, or about 2 toabout 12 hours, or about 3 to about 12 hours, or about 3 to about 8hours, or about 4 to about 10 hours, or about 4 to about 12 hours, orabout 4 to about 9 hours, or about 5 to about 8 hours

In some preferred embodiments, the invention comprises an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; a controlled release material to render said dosage formsuitable for extended release in a human patient.

In some preferred embodiments, the invention comprises an oral modifiedrelease pharmaceutical composition and method for the treatment ofbutorphanol responsive disorders comprising a therapeutically effectiveamount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof; a controlled release material torender said dosage form suitable for extended release in a humanpatient; said dosage form administered at a prespecified dosing regimen;said dosing regimen associated with reduced side effects, improvedtolerability and reduced treatment discontinuation due to side effects;said regimen comprising administering a dose of about 2 to 4 mg for 1 to7 days, followed by about 3 to 6 mg for a subsequent period of 1 to 7days, followed by >about 7 mg for duration of treatment; or about 4 to 6mg for 1 to 7 days, followed by about 5 to 8 mg for a subsequent periodof 1 to 7 days, followed by >about 8 mg for duration of treatment; orabout 6 to 8 mg for 1 to 7 days, followed by about 9 to 12 mg for asubsequent period of 1 to 7 days, followed by >about 9 mg for durationof treatment; or about 4 to 8 mg for 1 to 7 days, followed by about 9 to12 mg for a subsequent period of 1 to 7 days, followed by >about 9 mgfor duration of treatment; or about 8 mg for 1 to 7 days, followed byabout 9 to 12 mg for a subsequent period of 1 to 7 days, followedby >about 9 mg for duration of treatment; or about 8 mg for 1 to 7 days,followed by about 9 to 16 mg for a subsequent period of 1 to 7 days,followed by >about 9 mg for duration of treatment; or about 2.5 to 5 mgfor 1 to 7 days, followed by about 3 to 10 mg for a subsequent period of1 to 7 days, followed by >about 3 mg for duration of treatment; or about4 mg for 1 to 7 days, followed by about 6 mg for a subsequent period of1 to 7 days, followed by >about 6 mg for duration of treatment; or about4 for 1 to 7 days, followed by about 6 to 8 mg for a subsequent periodof 1 to 7 days, followed by >about 6 mg for duration of treatment; orabout 4 mg for 1 to 7 days, followed by about 8 mg for a subsequentperiod of 1 to 7 days, followed by >about 9 mg for duration oftreatment; or about 8 mg for 1 to 7 days, followed by >about 9 mg forduration of treatment; or about 2 to 4 mg for 4 days, followed by about3 to 8 mg for a subsequent period of 4 days, followed by >about 4 mg forduration of treatment; or about 8 mg for 4 to 7 days, followed by about9 to 16 mg for a subsequent period of 4 to 7 days, followed by >about 9mg for duration of treatment; or about 5 mg for 4 to 7 days, followed byabout 10 to 15 mg for a subsequent period of 1 to 7 days, followedby >about 10 mg for duration of treatment.

In some preferred embodiments, the invention comprises an oral modifiedrelease pharmaceutical composition and method for the treatment ofbutorphanol responsive disorders comprising a therapeutically effectiveamount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof; a controlled release material torender said dosage form suitable for extended release in a humanpatient; said dosage form administered at a prespecified dosing regimen;said dosing regimen associated with reduced side effects, improvedtolerability and reduced treatment discontinuation due to side effects;said regimen comprising administering a total daily dose of about 4 to10 mg for 1 to 7 days, followed by about 5 to 15 mg for a subsequentperiod of 1 to 7 days, followed by >about 10 mg for duration oftreatment; or about 5 to 20 mg for 1 to 7 days, followed by about 5 to30 mg for a subsequent period of 1 to 7 days, followed by >about 10 mgfor duration of treatment; or about 10 to 20 mg for 1 to 7 days,followed by about 10 to 30 mg for a subsequent period of 1 to 7 days,followed by >about 15 mg for duration of treatment; or about 10 to 20 mgfor 1 to 7 days, followed by about 10 to 40 mg for a subsequent periodof 1 to 7 days, followed by >about 15 mg for duration of treatment; orabout 10 to 20 mg for 1 to 7 days, followed by about 10 to 40 mg for asubsequent period of 1 to 7 days, followed by >about 20 mg for durationof treatment; or about 15 to 30 mg for 1 to 7 days, followed by about 15to 40 mg for a subsequent period of 1 to 7 days, followed by >about 20mg for duration of treatment; or about 15 to 30 mg for 1 to 7 days,followed by about 15 to 40 mg for a subsequent period of 1 to 7 days,followed by >about 30 mg for duration of treatment;

or about 15 to 40 mg for 1 to 7 days, followed by about 20 to 40 mg fora subsequent period of 1 to 7 days, followed by >about 25 mg forduration of treatment; or about 15 to 40 mg for 1 to 7 days, followed byabout 20 to 50 mg for a subsequent period of 1 to 7 days, followedby >about 30 mg for duration of treatment; or about 15 to 40 mg for 1 to7 days, followed by about 20 to 60 mg for a subsequent period of 1 to 7days, followed by >about 30 mg for duration of treatment; or about 20 to60 mg for 1 to 7 days, followed by about 20 to 80 mg for a subsequentperiod of 1 to 7 days, followed by >about 30 mg for duration oftreatment; or about 20 to 60 mg for 1 to 7 days, followed by about 30 to80 mg for a subsequent period of 1 to 7 days, followed by >about 30 mgfor duration of treatment; or about 20 to 60 mg for 1 to 7 days,followed by about 30 to 80 mg for a subsequent period of 1 to 7 days,followed by >about 40 mg for duration of treatment; or about 25 to 50 mgfor 1 to 7 days, followed by about 25 to 100 mg for a subsequent periodof 1 to 7 days, followed by >about 30 mg for duration of treatment; orabout 25 to 50 mg for 1 to 7 days, followed by about 25 to 100 mg for asubsequent period of 1 to 7 days, followed by >about 40 mg for durationof treatment; or about 25 to 50 mg for 1 to 7 days, followed by about 50to 100 mg for a subsequent period of 1 to 7 days, followed by >about 50mg for duration of treatment; or about 10 to 40 mg for 1 to 7 days,followed by about 20 to 40 mg for a subsequent period of 1 to 7 days,followed by >about 30 mg for duration of treatment; or about 10 to 40 mgfor 1 to 7 days, followed by about 20 to 60 mg for a subsequent periodof 1 to 7 days, followed by >about 30 mg for duration of treatment; orabout 10 to 40 mg for 1 to 7 days, followed by about 20 to 60 mg for asubsequent period of 1 to 7 days, followed by >about 40 mg for durationof treatment; or about 10 to 40 mg for 1 to 7 days, followed by >about20 mg for duration of treatment; or about 10 to 40 mg for 1 to 7 days,followed by >about 30 mg for duration of treatment; or about 10 to 50 mgfor 1 to 7 days, followed by >about 20 mg for duration of treatment; orabout 10 to 50 mg for 1 to 7 days, followed by >about 30 mg for durationof treatment; or about 15 to 40 mg for 1 to 7 days, followed by >about30 mg for duration of treatment; or about 15 to 50 mg for 1 to 7 days,followed by >about 30 mg for duration of treatment; or about 20 to 60 mgfor 1 to 7 days, followed by >about 25 mg for duration of treatment; orabout 20 to 60 mg for 1 to 7 days, followed by >about 30 mg for durationof treatment; or about 20 to 60 mg for 1 to 7 days, followed by >about40 mg for duration of treatment; or about 20 to 60 mg for 1 to 7 days,followed by >about 25 mg for duration of treatment; or about 5 to 60 mgfor the duration of treatment; or about 5 to 80 mg for the duration oftreatment; or about 5 to 120 mg for the duration of treatment; or about5 to 160 mg for the duration of treatment; or about 10 to 60 mg for theduration of treatment; or about 10 to 80 mg for the duration oftreatment; or about 10 to 120 mg for the duration of treatment; or about10 to 160 mg for the duration of treatment; or about 10 to 200 mg forthe duration of treatment;or about 20 to 60 mg for the duration of treatment; or about 20 to 80 mgfor the duration of treatment; or about 20 to 120 mg for the duration oftreatment; or about 20 to 160 mg for the duration of treatment; or about20 to 200 mg for the duration of treatment; or about 25 to 100 mg forthe duration of treatment; or about 25 to 150 mg for the duration oftreatment; or about 25 to 200 mg for the duration of treatment.

In some preferred embodiments, the invention comprises an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof; said dosage from providing a C_(min)of butorphanol of about 0 ng/mL to about 20 ng/mL or 0.01 ng/mL to about20 ng/mL. In other preferred embodiments, the dosage form provides aC_(min) of butorphanol of less than about 18 ng/mL, or less than about15 ng/mL, or less than about 14 ng/mL, or less than about 12 ng/mL, orless than about 10 ng/mL, or less than about 8 ng/mL, or less than about7 ng/mL, or less than about 6 ng/mL, or less than about 5 ng/mL, or lessthan about 4 ng/mL, or less than about 3 ng/mL, or less than about 2ng/mL, or less than about 1.5 ng/mL, or less than about 1 ng/mL, or lessthan about 0.7 ng/mL, or less than about 0.6 ng/mL, or less than about0.5 ng/mL, or less than about 0.4 ng/mL, or less than about 0.3 ng/mL,or less than about 0.2 ng/mL, or less than about 0.1 ng/mL, or less thanabout 0.05 ng/mL.

In some preferred embodiments, the invention comprises an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; said dosage from providing a C_(min) of butorphanolmeasured from a mean of about 0.5 to about 30 hours. In other preferredembodiments, the dosage form provides a C_(min) of butorphanol measuredfrom a mean of about 0.5 to about 28 hours, or about 1 to about 28hours, or about 1 to 24 hours, or about 1 to about 20 hours, or about 1to about 18 hours, or about 1 to about 16 hours, or about 1 to about 12hours, or about 1 to 10 hours, or about 1 to about 8 hours, or about 1to about 6 hours, or about 1 to about 4 hours, about 2 to about 24hours, or about 3 to 24 hours, or about 4 to about 24 hours, or about 6to about 24 hours, or about 8 to about 24 hours, about 2 to about 12hours, or about 3 to 10 hours, or about 3 to about 8 hours, or about 4to about 8 hours, or about 6 to about 10 hours. In some preferredembodiments, the aforementioned C_(min) being achieved with oralpharmaceutical compositions comprising a controlled release material torender said dosage form extended release, or delayed onset, extendedrelease, or delayed onset, rapid release, or delayed onset, pulsatilerelease.

In some preferred embodiments, the invention comprises an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof; said dosage form providing a systemicexposure as assessed by the mean of butorphanol area under the plasmaconcentration time curves to 24 hours post-dose (AUC₀₋₂₄) of about 0.1ng·hr/mL to about 600 ng·hr/mL. In other preferred embodiments, thedosage form provides an AUC₀₋₂₄ of butorphanol of about 0.2 ng·hr/mL toabout 600 ng·hr/mL, or about 0.3 ng·hr/mL to about 600 ng·hr/mL, orabout 0.5 ng·hr/mL to about 600 ng·hr/mL, or about 0.7 ng·hr/mL to about600 ng·hr/mL, or about 1 ng·hr/mL to about 600 ng·hr/mL, or about 2ng·hr/mL to about 600 ng·hr/mL, or about 3 ng·hr/mL to about 600ng·hr/mL, or about 4 ng·hr/mL to about 600 ng·hr/mL, or about 5 ng·hr/mLto about 600 ng·hr/mL, or about 6 ng·hr/mL to about 600 ng·hr/mL, orabout 7 ng·hr/mL to about 600 ng·hr/mL, or about 8 ng·hr/mL to about 600ng·hr/mL, or about 9 ng·hr/mL to about 600 ng·hr/mL, or about 10ng·hr/mL to about 600 ng·hr/mL, or about 12 ng·hr/mL to about 600ng·hr/mL, or about 14 ng·hr/mL to about 600 ng·hr/mL, or about 15ng·hr/mL to about 600 ng·hr/mL, or about 17 ng·hr/mL to about 600ng·hr/mL, or about 20 ng·hr/mL to about 600 ng·hr/mL, or about 0.1ng·hr/mL to about 550 ng·hr/mL, or about 0.1 ng·hr/mL to about 500ng·hr/mL, or about 0.1 ng·hr/mL to about 450 ng·hr/mL, or about 0.1ng·hr/mL to about 400 ng·hr/mL, or about 0.1 ng·hr/mL to about 350ng·hr/mL, or about 0.1 ng·hr/mL to about 300 ng·hr/mL, or about 0.1ng·hr/mL to about 250 ng·hr/mL, or about 0.1 ng·hr/mL to about 200ng·hr/mL, or about 0.1 ng·hr/mL to about 175 ng·hr/mL, or about 0.1ng·hr/mL to about 150 ng·hr/mL, or about 0.1 ng·hr/mL to about 125ng·hr/mL, or about 0.1 ng·hr/mL to about 100 ng·hr/mL, or about 0.1ng·hr/mL to about 90 ng·hr/mL, or about 0.1 ng·hr/mL to about 80ng·hr/mL, or about 0.1 ng·hr/mL to about 70 ng·hr/mL, or about 0.1ng·hr/mL to about 60 ng·hr/mL, or about 0.1 ng·hr/mL to about 55ng·hr/mL, or about 0.1 ng·hr/mL to about 50 ng·hr/mL, or about 0.1ng·hr/mL to about 45 ng·hr/mL, or about 0.1 ng·hr/mL to about 40ng·hr/mL, or about 0.1 ng·hr/mL to about 35 ng·hr/mL, or about 0.1ng·hr/mL to about 30 ng·hr/mL, or about 0.1 ng·hr/mL to about 28ng·hr/mL, or about 0.1 ng·hr/mL to about 25 ng·hr/mL, or about 0.1ng·hr/mL to about 22 ng·hr/mL, or about 0.1 ng·hr/mL to about 20ng·hr/mL, or about 0.1 ng·hr/mL to about 18 ng·hr/mL, or about 0.1ng·hr/mL to about 15 ng·hr/mL, or about 0.1 ng·hr/mL to about 12ng·hr/mL, or about 0.1 ng·hr/mL to about 10 ng·hr/mL, or about 1ng·hr/mL to about 100 ng·hr/mL, or about 1 ng·hr/mL to about 75ng·hr/mL, or about 1 ng·hr/mL to about 50 ng·hr/mL, or about 2 ng·hr/mLto about 100 ng·hr/mL, or about 2 ng·hr/mL to about 75 ng·hr/mL, orabout 2 ng·hr/mL to about 50 ng·hr/mL, or about 4 ng·hr/mL to about 100ng·hr/mL, or about 4 ng·hr/mL to about 75 ng·hr/mL, or about 4 ng·hr/mLto about 50 ng·hr/mL, or about 1 ng·hr/mL to about 30 ng·hr/mL, or about2 ng·hr/mL to about 30 ng·hr/mL, or about 3 ng·hr/mL to about 30ng·hr/mL, or about 1 ng·hr/mL to about 20 ng·hr/mL, or about 1 ng·hr/mLto about 15 ng·hr/mL, or about 5 ng·hr/mL to about 40 ng·hr/mL, or about8 ng·hr/mL to about 40 ng·hr/mL, or about 10 ng·hr/mL to about 40ng·hr/mL, or about 10 ng·hr/mL to about 300 ng·hr/mL, or about 12ng·hr/mL to about 300 ng·hr/mL, or about 14 ng·hr/mL to about 300ng·hr/mL, or about 15 ng·hr/mL to about 300 ng·hr/mL, or about 16ng·hr/mL to about 300 ng·hr/mL, or about 17 ng·hr/mL to about 300ng·hr/mL, or about 18 ng·hr/mL to about 300 ng·hr/mL, or about 19ng·hr/mL to about 300 ng·hr/mL, or about 20 ng·hr/mL to about 300ng·hr/mL, or about 22 ng·hr/mL to about 300 ng·hr/mL, or about 24ng·hr/mL to about 300 ng·hr/mL, or about 26 ng·hr/mL to about 300ng·hr/mL, or about 28 ng·hr/mL to about 300 ng·hr/mL, or about 30ng·hr/mL to about 300 ng·hr/mL. In other preferred embodiments, thedosage form provides an AUC₀₋₂₄ of butorphanol of about 2 ng·hr/mL toabout 60 ng·hr/mL, or about 2 ng·hr/mL to about 120 ng·hr/mL, or about 2ng·hr/mL to about 180 ng·hr/mL, or about 4 ng·hr/mL to about 60ng·hr/mL, or about 4 ng·hr/mL to about 120 ng·hr/mL, or about 4 ng·hr/mLto about 180 ng·hr/mL. In particularly preferred embodiments, the dosageform provides an AUC₀₋₂₄ of butorphanol of about 8 ng·hr/mL to about 60ng·hr/mL, or about 12 ng·hr/mL to about 60 ng·hr/mL, or about 16ng·hr/mL to about 60 ng·hr/mL, or about 8 ng·hr/mL to about 100ng·hr/mL, or about 12 ng·hr/mL to about 100 ng·hr/mL, or about 20ng·hr/mL to about 100 ng·hr/mL.

In some preferred embodiments, the invention comprises an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof; said dosage form providing a systemicexposure as assessed by the mean butorphanol area under the plasmaconcentration time curve to infinity (AUC_(0-inf)) of about 0.1 ng·hr/mLto about 600 ng·hr/mL. In other preferred embodiments, the dosage formprovides an AUC_(0-inf) of butorphanol of about 0.2 ng·hr/mL to about600 ng·hr/mL, or about 0.3 ng·hr/mL to about 600 ng·hr/mL, or about 0.5ng·hr/mL to about 600 ng·hr/mL, or about 0.7 ng·hr/mL to about 600ng·hr/mL, or about 1 ng·hr/mL to about 600 ng·hr/mL, or about 2 ng·hr/mLto about 600 ng·hr/mL, or about 3 ng·hr/mL to about 600 ng·hr/mL, orabout 4 ng·hr/mL to about 600 ng·hr/mL, or about 5 ng·hr/mL to about 600ng·hr/mL, or about 6 ng·hr/mL to about 600 ng·hr/mL, or about 7 ng·hr/mLto about 600 ng·hr/mL, or about 8 ng·hr/mL to about 600 ng·hr/mL, orabout 9 ng·hr/mL to about 600 ng·hr/mL, or about 10 ng·hr/mL to about600 ng·hr/mL, or about 12 ng·hr/mL to about 600 ng·hr/mL, or about 14ng·hr/mL to about 600 ng·hr/mL, or about 15 ng·hr/mL to about 600ng·hr/mL, or about 17 ng·hr/mL to about 600 ng·hr/mL, or about 20ng·hr/mL to about 600 ng·hr/mL, or about 0.1 ng·hr/mL to about 550ng·hr/mL, or about 0.1 ng·hr/mL to about 500 ng·hr/mL, or about 0.1ng·hr/mL to about 450 ng·hr/mL, or about 0.1 ng·hr/mL to about 400ng·hr/mL, or about 0.1 ng·hr/mL to about 350 ng·hr/mL, or about 0.1ng·hr/mL to about 300 ng·hr/mL, or about 0.1 ng·hr/mL to about 250ng·hr/mL, or about 0.1 ng·hr/mL to about 200 ng·hr/mL, or about 0.1ng·hr/mL to about 175 ng·hr/mL, or about 0.1 ng·hr/mL to about 150ng·hr/mL, or about 0.1 ng·hr/mL to about 125 ng·hr/mL, or about 0.1ng·hr/mL to about 100 ng·hr/mL, or about 0.1 ng·hr/mL to about 90ng·hr/mL, or about 0.1 ng·hr/mL to about 80 ng·hr/mL, or about 0.1ng·hr/mL to about 70 ng·hr/mL, or about 0.1 ng·hr/mL to about 60ng·hr/mL, or about 0.1 ng·hr/mL to about 55 ng·hr/mL, or about 0.1ng·hr/mL to about 50 ng·hr/mL, or about 0.1 ng·hr/mL to about 45ng·hr/mL, or about 0.1 ng·hr/mL to about 40 ng·hr/mL, or about 0.1ng·hr/mL to about 35 ng·hr/mL, or about 0.1 ng·hr/mL to about 30ng·hr/mL, or about 0.1 ng·hr/mL to about 28 ng·hr/mL, or about 0.1ng·hr/mL to about 25 ng·hr/mL, or about 0.1 ng·hr/mL to about 22ng·hr/mL, or about 0.1 ng·hr/mL to about 20 ng·hr/mL, or about 0.1ng·hr/mL to about 18 ng·hr/mL, or about 0.1 ng·hr/mL to about 15ng·hr/mL, or about 0.1 ng·hr/mL to about 12 ng·hr/mL, or about 0.1ng·hr/mL to about 10 ng·hr/mL, or about 1 ng·hr/mL to about 100ng·hr/mL, or about 1 ng·hr/mL to about 75 ng·hr/mL, or about 1 ng·hr/mLto about 50 ng·hr/mL, or about 2 ng·hr/mL to about 100 ng·hr/mL, orabout 2 ng·hr/mL to about 75 ng·hr/mL, or about 2 ng·hr/mL to about 50ng·hr/mL, or about 4 ng·hr/mL to about 100 ng·hr/mL, or about 4 ng·hr/mLto about 75 ng·hr/mL, or about 4 ng·hr/mL to about 50 ng·hr/mL, or about1 ng·hr/mL to about 30 ng·hr/mL, or about 2 ng·hr/mL to about 30ng·hr/mL, or about 3 ng·hr/mL to about 30 ng·hr/mL, or about 1 ng·hr/mLto about 20 ng·hr/mL, or about 1 ng·hr/mL to about 15 ng·hr/mL, or about5 ng·hr/mL to about 40 ng·hr/mL, or about 8 ng·hr/mL to about 40ng·hr/mL, or about 10 ng·hr/mL to about 40 ng·hr/mL, or about 10ng·hr/mL to about 300 ng·hr/mL, or about 12 ng·hr/mL to about 300ng·hr/mL, or about 14 ng·hr/mL to about 300 ng·hr/mL, or about 15ng·hr/mL to about 300 ng·hr/mL, or about 16 ng·hr/mL to about 300ng·hr/mL, or about 17 ng·hr/mL to about 300 ng·hr/mL, or about 18ng·hr/mL to about 300 ng·hr/mL, or about 19 ng·hr/mL to about 300ng·hr/mL, or about 20 ng·hr/mL to about 300 ng·hr/mL, or about 22ng·hr/mL to about 300 ng·hr/mL, or about 24 ng·hr/mL to about 300ng·hr/mL, or about 26 ng·hr/mL to about 300 ng·hr/mL, or about 28ng·hr/mL to about 300 ng·hr/mL, or about 30 ng·hr/mL to about 300ng·hr/mL. In other preferred embodiments, the dosage form provides anAUC_(0-inf) of butorphanol of about 2 ng·hr/mL to about 60 ng·hr/mL, orabout 2 ng·hr/mL to about 120 ng·hr/mL, or about 2 ng·hr/mL to about 180ng·hr/mL, or about 4 ng·hr/mL to about 60 ng·hr/mL, or about 4 ng·hr/mLto about 120 ng·hr/mL, or about 4 ng·hr/mL to about 180 ng·hr/mL. Inparticularly preferred embodiments, the dosage form provides anAUC_(0-inf) of butorphanol of about 8 ng·hr/mL to about 60 ng·hr/mL, orabout 12 ng·hr/mL to about 60 ng·hr/mL, or about 16 ng·hr/mL to about 60ng·hr/mL, or about 8 ng·hr/mL to about 100 ng·hr/mL, or about 12ng·hr/mL to about 100 ng·hr/mL, or about 20 ng·hr/mL to about 100ng·hr/mL.

In some preferred embodiments, the invention comprises an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof; said dosage form providing a systemicexposure as assessed by the mean butorphanol area under the plasmaconcentration time curve (AUC₀₋₂₄) of up to 600 ng·hr/mL, or up to 500ng·hr/mL, or up to 400 ng·hr/mL, or up to 350 ng·hr/mL, or up to 300ng·hr/mL, or up to 250 ng·hr/mL, or up to 200 ng·hr/mL, or up to 175ng·hr/mL, or up to 150 ng·hr/mL, or up to 125 ng·hr/mL, or up to 100ng·hr/mL, or up to 90 ng·hr/mL, or up to 80 ng·hr/mL, or up to 70ng·hr/mL, up to 60 ng·hr/mL, or up to 50 ng·hr/mL, or up to 45 ng·hr/mL,or up to 40 ng·hr/mL, or up to 35 ng·hr/mL, or up to 30 ng·hr/mL, or upto 25 ng·hr/mL, or up to 20 ng·hr/mL, or up to 18 ng·hr/mL, or up to 16ng·hr/mL, or up to 15 ng·hr/mL, up to 60 ng·hr/mL, or up to 14 ng·hr/mL,or up to 12 ng·hr/mL, or up to 10 ng·hr/mL. In other preferredembodiments, the dosage form provides an AUC₀₋₂₄ of butorphanol of up to40 ng·hr/mL, or up to 50 ng·hr/mL, or up to 60 ng·hr/mL, or up to 80ng·hr/mL, or up to 100 ng·hr/mL, up to 120 ng·hr/mL, or up to 140ng·hr/mL, or up to 160 ng·hr/mL, or up to 200 ng·hr/mL. In particularlypreferred embodiments, the dosage form provides an AUC₀₋₂₄ ofbutorphanol of up to 40 ng·hr/mL, or up to 60 ng·hr/mL, or up to 80ng·hr/mL, or up to 100 ng·hr/mL, up to 120 ng·hr/mL, or up to 140ng·hr/mL, or up to 180 ng·hr/mL.

In some preferred embodiments, the invention comprises an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof; said dosage form providing a systemicexposure as assessed by the mean butorphanol area under the plasmaconcentration time curve (AUC₀₋₂₄) of not less than about 60 ng·hr/mL,or not less than about 50 ng·hr/mL, or not less than about 45 ng·hr/mL,or not less than about 40 ng·hr/mL, or not less than about 35 ng·hr/mL,or not less than about 30 ng·hr/mL, or not less than about 25 ng·hr/mL,or not less than about 20 ng·hr/mL, or not less than about 18 ng·hr/mL,or not less than about 16 ng·hr/mL, or not less than about 15 ng·hr/mL,or not less than about 14 ng·hr/mL, or not less than about 12 ng·hr/mL,or not less than about 11 ng·hr/mL, or not less than about 10 ng·hr/mL,or not less than about 8 ng·hr/mL, or not less than about 7 ng·hr/mL, ornot less than about 6 ng·hr/mL, or not less than about 5 ng·hr/mL, ornot less than about 4 ng·hr/mL.

In some preferred embodiments, the invention comprises an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof; said dosage form providing a systemicexposure as assessed by the mean butorphanol area under the plasmaconcentration time curve (AUC_(0-inf)) of up to 600 ng·hr/mL, or up to500 ng·hr/mL, or up to 400 ng·hr/mL, or up to 350 ng·hr/mL, or up to 300ng·hr/mL, or up to 250 ng·hr/mL, or up to 200 ng·hr/mL, or up to 175ng·hr/mL, or up to 150 ng·hr/mL, or up to 125 ng·hr/mL, or up to 100ng·hr/mL, or up to 90 ng·hr/mL, or up to 80 ng·hr/mL, or up to 70ng·hr/mL, up to 60 ng·hr/mL, or up to 50 ng·hr/mL, or up to 45 ng·hr/mL,or up to 40 ng·hr/mL, or up to 35 ng·hr/mL, or up to 30 ng·hr/mL, or upto 25 ng·hr/mL, or up to 20 ng·hr/mL, or up to 18 ng·hr/mL, or up to 16ng·hr/mL, or up to 15 ng·hr/mL, up to 60 ng·hr/mL, or up to 14 ng·hr/mL,or up to 12 ng·hr/mL, or up to 10 ng·hr/mL. In other preferredembodiments, the dosage form provides an AUC_(0-inf) of butorphanol ofup to 40 ng·hr/mL, or up to 50 ng·hr/mL, or up to 60 ng·hr/mL, or up to80 ng·hr/mL, or up to 100 ng·hr/mL, up to 120 ng·hr/mL, or up to 140ng·hr/mL, or up to 160 ng·hr/mL, or up to 200 ng·hr/mL. In particularlypreferred embodiments, the dosage form provides an AUC_(0-inf) ofbutorphanol of up to 40 ng·hr/mL, or up to 60 ng·hr/mL, or up to 80ng·hr/mL, or up to 100 ng·hr/mL, up to 120 ng·hr/mL, or up to 140ng·hr/mL, or up to 120 ng·hr/mL.

In some preferred embodiments, the invention comprises an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof; said dosage form providing a systemicexposure as assessed by the mean butorphanol area under the plasmaconcentration time curve (AUC_(0-inf)) of not less than about 60ng·hr/mL, or not less than about 50 ng·hr/mL, or not less than about 45ng·hr/mL, or not less than about 40 ng·hr/mL, or not less than about 35ng·hr/mL, or not less than about 30 ng·hr/mL, or not less than about 25ng·hr/mL, or not less than about 20 ng·hr/mL, or not less than about 18ng·hr/mL, or not less than about 16 ng·hr/mL, or not less than about 15ng·hr/mL, or not less than about 14 ng·hr/mL, or not less than about 12ng·hr/mL, or not less than about 11 ng·hr/mL, or not less than about 10ng·hr/mL.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; said dosage form providing at least 80% of the steadystate therapeutic concentration of butorphanol after administration of≦3, or ≦4, or ≦5, or ≦6 doses at their intended dosing frequency.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; said dosage form after administration to a human patientproviding a C_(min)/C_(max) ratio of butorphanol of 0.1 to about 1.25.In other preferred embodiments, the dosage form provides aC_(min)/C_(max) ratio of butorphanol of about 0.1 to about 1.15, about0.1 to about 1.19, about 0.1 to about 1, about 0.1 to about 0.9, about0.1 to about 0.85, or about 0.1 to about 0.8, or about 0.1 to about 0.7,or about 0.1 to about 0.6, or about 0.1 to about 0.5, or about 0.1 toabout 0.4, or about 0.1 to about 0.3, or about 0.2 to about 1.0, orabout 0.25 to about 1.25, or about 0.25 to about 1.25, or about 0.4 toabout 1.25, or about 0.5 to about 1.25, or about 0.65 to about 1.25, orabout 0.75 to about 1.25, or about 0.2 to about 0.9, or about 0.3 toabout 0.9, or about 0.3 to about 0.8, or about 0.4 to about 0.8, orabout 0.4 to about 0.7, or about 0.4 to about 0.6.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; said dosage form after administration to a human patientproviding a percent fluctuation of butorphanol of less than 400%. Inother preferred embodiments, the dosage form provides a percentfluctuation of butorphanol of less than 350%, or less than 300%, or lessthan 250%, or less than 200%, or less than 150%, or less than 100%, orless than 75%, or less than 50%, or less than 25%.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; said dosage form after administration to a human patientproviding a W₅₀ of butorphanol of about 1 to about 6 hours for each 6hour time period of intended dosing frequency and intended duration ofaction. In other preferred embodiments, the dosage form provides a W₅₀of butorphanol for each 6 hour time period of intended dosing frequencyand intended duration of action of about 1 to about 5 hours, or about 1to about 4 hours, or about 1 to about 3 hours, or about 1 to about 2hours, or 2 to about 6 hours, or about 3 to about 6 hours, or about 4 toabout 6 hours, or about 2 to about 4 hours.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; said dosage form after administration to a human patientproviding a HVD of butorphanol of about 1.5 to about 6 hours for each 6hour time period of intended dosing frequency and intended duration ofaction. In other preferred embodiments, the dosage form provides a HVDof butorphanol for each 6 hour time period of intended dosing frequencyand intended duration of action of about 1.5 to about 5 hours, or about1.5 to about 4 hours, or about 1.5 to about 3 hours, or about 1.5 toabout 2 hours, or 2 to about 6 hours, or about 3 to about 6 hours, orabout 4 to about 6 hours, or about 2 to about 4 hours.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; said dosage form after administration to a human patientproviding an AI of butorphanol of not more than 4.0. In other preferredembodiments, the dosage form provides an AI of butorphanol of not morethan about 3.5, or not more than about 3.0, or not more than about 2.5,or not more than about 2, or not more than about 1.75, or not more thanabout 1.5, or not more than about 1.25, or not more than about 1, or notmore than about 0.75, or not more than about 0.5, or not more than about0.25.

In some preferred embodiments, the in vivo pharmacokinetic parameters ofthe specifications, embodiments and claims are achieved with oralpharmaceutical compositions comprising a controlled release material torender said dosage form suitable for extended release.

In some preferred embodiments, the specifications and claims areachieved with oral pharmaceutical compositions comprising a controlledrelease material to render said dosage form suitable for extendedrelease.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; and a controlled release material with gastroretentiveproperties to render said dosage form suitable for extended release oraladministration to a human patient.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; and a controlled release material with osmotic releaseto render said dosage form suitable for extended release oraladministration to a human patient.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; and a controlled release material with zero-order orpseudo-zero-order release to render said dosage form suitable forextended release oral administration to a human patient.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and a controlled release material to render said dosageform suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day(Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24Hor Q24H PRN) administration to a human patient, said dosage form afteradministration to a human patient providing a percent fluctuation ofbutorphanol of less than 400%. In other preferred embodiments, thedosage form provides a percent fluctuation of butorphanol of less thanabout 375%, or less than about 350%, or less than about 325%, or lessthan about 300%, or less than about 275%, or less than about 250%, orless than about 225%, or less than about 200%, or less than about 175%,or less than about 150%, or less than about 125%, or less than about100%, or less than about 75%, or less than about 50%, or less than about25%.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and controlled release material to render said dosageform suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day(Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24Hor Q24H PRN) administration to a human patient, said dosage form afteradministration to a human patient, providing an AI of butorphanol of notmore than 4.0. In other preferred embodiments, the dosage form providesan AI of butorphanol of not more than about 3.75, or not more than about3.5, or not more than about 3.25, or not more than about 3, or not morethan about 2.75, or not more than about 2.5, or not more than about 2,or not more than about 1.5, not more than about 1.25, or not more thanabout 1, or not more than about 0.75.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for three times-a-day (Q8H or Q8H PRN),twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a mean butorphanol C_(max) of about 0.025ng/mL to about 30 ng/mL. In other preferred embodiments, the dosage formprovides a C_(max) of butorphanol of about 0.05 ng/mL to about 30 ng/mL,or about 0.75 ng/mL to about 30 ng/mL, or about 0.1 ng/mL to about 30ng/mL, or about 0.2 ng/mL to about 30 ng/mL, or about 0.3 ng/mL to about30 ng/mL, or about 0.4 ng/mL to about 30 ng/mL, or about 0.05 ng/mL toabout 25 ng/mL, or about 0.05 ng/mL to about 20 ng/mL, or about 0.05ng/mL to about 18 ng/mL, or about 0.05 ng/mL to about 15 ng/mL, or about0.05 ng/mL to about 12 ng/mL, or about 0.05 ng/mL to about 10 ng/mL, orabout 0.05 ng/mL to about 8 ng/mL, or about 0.05 ng/mL to about 7 ng/mL,or about 0.05 ng/mL to about 6 ng/mL, or about 0.05 ng/mL to about 5ng/mL, or about 0.05 ng/mL to about 4 ng/mL, or about 0.05 ng/mL toabout 3 ng/mL, or about 0.1 ng/mL to about 7 ng/mL, or about 0.1 ng/mLto about 6 ng/mL, or about 0.1 ng/mL to about 5 ng/mL, or about 0.1ng/mL to about 4 ng/mL, or about 0.1 ng/mL to about 3 ng/mL.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for three times-a-day (Q8H or Q8H PRN),twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a mean butorphanol C_(max) of less thanabout 30 ng/mL. In other preferred embodiments, the dosage form providesa C_(max) of butorphanol of less than about 28 ng/mL, or less than about25 ng/mL, or of less than about 28 ng/mL, or less than about 25 ng/mL,or less than about 23 ng/mL, or less than about 21 ng/mL, or less thanabout 20 ng/mL, or less than about 18 ng/mL, or less than about 15ng/mL, or less than about 12 ng/mL, or less than about 10 ng/mL, or lessthan about 9 ng/mL, or less than about 8 ng/mL, or less than about 7ng/mL, or less than about 6 ng/mL, or less than about 5 ng/mL, or lessthan about 4 ng/mL, or less than about 3 ng/mL, or less than about 2ng/mL, or less than about 1.5 ng/mL, or less than about 1.25 ng/mL, orless than about 1 ng/mL, or less than about 0.9 ng/mL, or less thanabout 0.8 ng/mL, or less than about 0.5 ng/mL, or less than about 0.4ng/mL, or less than about 0.2 ng/mL, or less than about 0.1 ng/mL.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for three times-a-day (Q8H or Q8H PRN),twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a mean butorphanol C_(max) of more thanabout 0.7 ng/mL. In other preferred embodiments, the dosage formprovides a C_(max) of butorphanol of more than about 0.8 ng/mL, or morethan about 0.9 ng/mL, or more than about 1 ng/mL, or more than about 1.1ng/mL, or more than about 1.2 ng/mL, or more than about 1.3 ng/mL, ormore than about 1.4 ng/mL, or more than about 1.5 ng/mL, or more thanabout 1.6 ng/mL, or more than about 1.7 ng/mL, or more than about 1.8ng/mL, or more than about 1.9 ng/mL, or more than about 2 ng/mL, or morethan about 2.1 ng/mL, or more than about 2.2 ng/mL, or more than about2.3 ng/mL, or more than about 2.4 ng/mL, or more than about 2.5 ng/mL,or more than about 2.6 ng/mL, or more than about 2.7 ng/mL, or more thanabout 2.8 ng/mL, or more than about 3 ng/mL, or more than about 3.25ng/mL, or more than about 3.5 ng/mL, or more than about 3.75 ng/mL, ormore than about 4 ng/mL, or more than about 4.25 ng/mL, or more thanabout 4.5.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for three times-a-day (Q8H or Q8H PRN),twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a mean butorphanol C_(min) of about 0 ng/mLto about 20 ng/mL or 0.01 ng/mL to about 20 ng/mL. In other preferredembodiments, the dosage form provides a C_(min) of butorphanol of lessthan about 18 ng/mL, or less than about 15 ng/mL, or less than about 14ng/mL, or less than about 12 ng/mL, or less than about 10 ng/mL, or lessthan about 8 ng/mL, or less than about 7 ng/mL, or less than about 6ng/mL, or less than about 5 ng/mL, or less than about 4 ng/mL, or lessthan about 3 ng/mL, or less than about 2 ng/mL, or less than about 1.5ng/mL, or less than about 1 ng/mL, or less than about 0.7 ng/mL, or lessthan about 0.6 ng/mL, or less than about 0.5 ng/mL, or less than about0.4 ng/mL, or less than about 0.3 ng/mL, or less than about 0.2 ng/mL,or less than about 0.1 ng/mL, or less than about 0.05 ng/mL.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for three times-a-day (Q8H or Q8H PRN),twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a mean butorphanol C_(min) of less thanabout 20 ng/mL. In other preferred embodiments, the dosage form providesa mean butorphanol C_(min) of less than about 18 ng/mL, or less thanabout 15 ng/mL, or less than about 12 ng/mL, or less than about 10ng/mL, or less than about 9 ng/mL, or less than about 8 ng/mL, or lessthan about 7 ng/mL, or less than about 5 ng/mL, or less than about 4ng/mL, or less than about 3 ng/mL, or less than about 2 ng/mL, or lessthan about 1 ng/mL, or less than about 0.8 ng/mL, or less than about 0.7ng/mL, or less than about 0.5 ng/mL, or less than about 0.4 ng/mL, orless than about 0.3 ng/mL, or less than about 0.2 ng/mL, or less thanabout 0.1 ng/mL, or less than about 0.05 ng/mL.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for three times-a-day (Q8H or Q8H PRN),twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a mean butorphanol C_(min) of greater thanabout 0.1 ng/mL, or greater than about 0.2 ng/mL, or greater than about0.4 ng/mL, or greater than about 0.5 ng/mL, or greater than about 0.6ng/mL, or greater than about 0.7 ng/mL, or greater than about 0.8 ng/mL,or greater than about 0.9 ng/mL, or greater than about 1 ng/mL, orgreater than about 1.1 ng/mL, or greater than about 1.2 ng/mL, orgreater than about 1.3 ng/mL, or greater than about 1.4 ng/mL, orgreater than about 1.5 ng/mL, or greater than about 1.6 ng/mL, orgreater than about 1.7 ng/mL, or greater than about 1.8 ng/mL.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol and, optionally, controlled releasematerial to render said dosage form suitable for four times-a-day (Q6Hor Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H orQ12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a humanpatient, said dosage form after administration to a human patientproviding a greater than about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,or 100% of the total absorbed dose into systemic circulation (asmeasured by bioavailability) during the first half of the intendeddosing frequency.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol and, optionally, controlled releasematerial to render said dosage form suitable for four times-a-day (Q6Hor Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H orQ12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a humanpatient, said dosage form after administration to a human patientproviding a greater than about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,or 100% of the total absorbed dose into systemic circulation (asmeasured by bioavailability) during the second half of the intendeddosing frequency.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol and, optionally, controlled releasematerial to render said dosage form suitable for four times-a-day (Q6Hor Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H orQ12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a humanpatient, said dosage form after administration to a human patientproviding a greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, or 100% of the total absorbed dose into systemic circulation(as measured by bioavailability) during the first one-third of theintended dosing frequency.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol and, optionally, controlled releasematerial to render said dosage form suitable for four times-a-day (Q6Hor Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H orQ12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a humanpatient, said dosage form after administration to a human patientproviding a greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, or 100% of the total absorbed dose into systemic circulation(as measured by bioavailability) during the last one-third of theintended dosing frequency.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol and, optionally, controlled releasematerial to render said dosage form suitable for four times-a-day (Q6Hor Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H orQ12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a humanpatient, said dosage form after administration to a human patientproviding a greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, or 100% of the total absorbed dose into systemic circulation(as measured by bioavailability) during the first one-quarter of theintended dosing frequency.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol and, optionally, controlled releasematerial to render said dosage form suitable for four times-a-day (Q6Hor Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H orQ12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a humanpatient, said dosage form after administration to a human patientproviding a greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, or 100% of the total absorbed dose into systemic circulation(as measured by bioavailability) during the last one-quarter of theintended dosing frequency.

In some preferred embodiments, in order to attain the specifications andclaims of the invention, it is necessary or critical to incorporate acontrolled release material in the dosage form.

In some preferred embodiments, the aforementioned embodiments whichprovide a greater amount of the total absorbed dose into systemiccirculation (as measured by bioavailability) during the first half,first one-third or first one quarter of the intended dosing frequencyresult in reduced frequency or duration of butorphanol related sideeffects.

In some preferred embodiments, the aforementioned embodiments whichprovide a greater amount of the total absorbed dose into systemiccirculation (as measured by bioavailability) during the second half,last one-third or last one quarter of the intended dosing frequencyresult in reduced frequency or duration of butorphanol related sideeffects.

In some preferred embodiments, the dosage form comprises atherapeutically effective amount of oral butorphanol or apharmaceutically acceptable salt of butorphanol, or a mixture thereof,said dosage form suitable for four times-a-day (Q6H or Q6H PRN), threetimes-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) oronce-a-day (QD, Q24H or Q24H PRN) administration to a human patient,wherein the in vivo specifications, including pharmacokineticspecifications achieved with oral pharmaceutical compositions which aredevoid of a controlled release material to render said dosage formextended release.

In some preferred embodiments, the dosage form comprises atherapeutically effective amount of oral butorphanol or apharmaceutically acceptable salt of butorphanol, or a mixture thereof,said dosage form suitable for four times-a-day (Q6H or Q6H PRN), threetimes-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) oronce-a-day (QD, Q24H or Q24H PRN) administration to a human patient,wherein the in vitro specifications, including dissolution ratespecifications achieved with oral pharmaceutical compositions which aredevoid of a controlled release material to render said dosage formextended release.

In some embodiments, the pharmacokinetic parameters in thespecifications (e.g., AUC, Cmax) referring to “butorphanol” are alsoapplicable to hydroxybutorphanol alone.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol, said dosage form suitable for fourtimes-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN),twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, wherein the butorphanol C_(max) issubstantially independent of food intake in that a difference, at anygiven time, between the C_(max) of butorphanol administered in fastedstate and the C_(max) of butorphanol administered in fed state (using astandardized meal) is no greater than about 30%. In other preferredembodiments, said difference is no greater than about 25%, or 20%, or18%, or 15%, or 12%, or 10%, or 8%, or 5%.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol, said dosage form suitable for fourtimes-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN),twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, wherein the butorphanol C_(max) issubstantially independent of food intake in that a difference, at anygiven time, between the C_(max) of butorphanol administered in fastedstate and the C_(max) of butorphanol administered after a standardizedhigh fat meal is no greater than about 30%. In other preferredembodiments, said difference is no greater than about 25%, or 20%, or18%, or 15%, or 12%, or 10%, or 8%, or 5%.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol, said dosage form suitable for fourtimes-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN),twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, wherein the butorphanol C_(max) issubstantially independent of alcohol intake in that a difference, at anygiven time, between the C_(max) of butorphanol administered with about30 to about 240 mL of a 40% ethanol solution and the C_(max) ofbutorphanol administered without concurrent alcohol (i.e., in an alcoholfree state) is no greater than about 30%. In other preferredembodiments, said difference is no greater than about 25%, or 20%, or18%, or 15%, or 12%, or 10%, or 8%, or 5%.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol, said dosage form suitable for fourtimes-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN),twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, wherein the AUC₀₋₁₂, AUC₀₋₂₄ andAUC_(0-inf) after single-dose administration are substantiallyindependent of food intake in that a difference, at any given time,between the said AUC of butorphanol when the dosage form administered infasted state and the said AUC of butorphanol when the dosage form isadministered in fed state (using a standardized meal) is no greater thanabout 30%. In other preferred embodiments, said difference is no greaterthan about 25%, or 20%, or 18%, or 15%, or 12%, or 10%, or 8%, or 5%.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol, said dosage form suitable for fourtimes-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN),twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, wherein the butorphanol AUC₀₋₁₂,AUC₀₋₂₄ and AUC_(0-inf) is substantially independent of food intake inthat a difference, at any given time, between the said AUC whenadministered in fasted state and the AUC when administered after astandardized high fat meal is no greater than about 30%. In otherpreferred embodiments, said difference is no greater than about 25%, or20%, or 18%, or 15%, or 12%, or 10%, or 8%, or 5%.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol, said dosage form suitable for fourtimes-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN),twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, wherein the butorphanol AUC₀₋₁,AUC₀₋₂, and AUC₀₋₄ is substantially independent of alcohol intake inthat a difference, at any given time, between the said AUC whenadministered with about 30 to about 240 mL of a 40% ethanol solution andthe said AUC when administered without concurrent alcohol (i.e., in analcohol free state) is no greater than about 30%. In other preferredembodiments, said difference is no greater than about 25%, or 20%, or18%, or 15%, or 12%, or 10%, or 8%, or 5%.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol and, optionally, controlled releasematerial to render said dosage form suitable for three times-a-day (Q8Hor Q8H PRN) administration to a human patient, said dosage form afteradministration to a human patient providing a C_(max) of butorphanol at0.75 to about 7 hours; and said dosage form providing a therapeuticeffect for at least about 8 hours. In other preferred embodiments, thedosage form provides a C_(max) of butorphanol at about 0.75 to about 6.5hours or about 0.75 to about 6 hours, or about 0.75 to about 5 hours, orabout 0.75 to about 4 hours, or about 0.75 to about 3.5 hours, or about0.75 to about 3 hours, or 0.75 to about 2.5 hours, or about 0.75 toabout 2 hours, or about 0.75 to about 1.5 hours, or about 1 to about 7hours, or about 1.5 to about 7 hours, or about 2 to about 7 hours, orabout 2.5 to about 7 hours, or 3 to about 7 hours, or about 3.5 to about7 hours, or about 4 to about 7 hours, or about 4.5 to about 7 hours, orabout 5 to about 6 hours, or about 5.5 to about 7 hours, or about 2 toabout 6, or about 2.5 to about 5.5 hours, or about 3 to about 5 hours,or about 3 to about 6. In some preferred embodiments, the aforementionedC_(max) being achieved with oral pharmaceutical compositions devoid of acontrolled release material to render said dosage form extended release.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol and, optionally, controlled releasematerial to render said dosage form suitable for three times-a-day (Q8Hor Q8H PRN) administration to a human patient, said dosage form afteradministration to a human patient providing a C_(min) of butorphanol atabout 6 to about 10 hours; and said dosage form providing a therapeuticeffect for at least about 8 hours. In other preferred embodiments, thedosage form provides a C_(min) of butorphanol at about 6 to about 9hours, or about 6 to about 8.5 hours, or about 6 to about 8 hours, orabout 6 to about 7.5 hours, or about 6 to about 7 hours, or about 6.5 toabout 10 hours, or about 7 to about 10 hours, or about 8 to about 10hours, or about 8 hours. In some preferred embodiments, theaforementioned C_(min) being achieved with oral pharmaceuticalcompositions devoid of a controlled release material to render saiddosage form extended release.

In some preferred embodiments, the dosage form provides an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for three times-a-day (Q8H or Q8H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a mean butorphanol AUC_(0-inf) after firstadministration or AUC₀₋₈ at steady state of about 2 ng·hr/mL to about200 ng·hr/mL; and said dosage form providing a therapeutic effect for atleast about 8 hours. In other preferred embodiments, the dosage formprovides a mean butorphanol AUC_(0-inf) after first administration orAUC₀₋₈ at steady state of about 2 ng·hr/mL to about 175 ng·hr/mL, orabout 2 ng·hr/mL to about 150 ng·hr/mL, or about 2 ng·hr/mL to about 125ng·hr/mL, or about 2 ng·hr/mL to about 110 ng·hr/mL, or about 2 ng·hr/mLto about 90 ng·hr/mL, or about 2 ng·hr/mL to about 8 ng·hr/mL, or about2 ng·hr/mL to about 70 ng·hr/mL, or about 2 ng·hr/mL to about 60ng·hr/mL, or about 2 ng·hr/mL to about 50 ng·hr/mL, or about 2 ng·hr/mLto about 45 ng·hr/mL, or about 2 ng·hr/mL to about 40 ng·hr/mL, or about2 ng·hr/mL to about 35 ng·hr/mL, or about 2 ng·hr/mL to about 30ng·hr/mL, or about 2 ng·hr/mL to about 28 ng·hr/mL, or about 2 ng·hr/mLto about 25 ng·hr/mL, or about 2 ng·hr/mL to about 22 ng·hr/mL, or about2 ng·hr/mL to about 20 ng·hr/mL, or about 2 ng·hr/mL to about 18ng·hr/mL, or about 2 ng·hr/mL to about 16 ng·hr/mL, or about 2 ng·hr/mLto about 15 ng·hr/mL, or about 2 ng·hr/mL to about 14 ng·hr/mL, or about2 ng·hr/mL to about 12 ng·hr/mL, or about 2 ng·hr/mL to about 10ng·hr/mL, or about 2 ng·hr/mL to about 9 ng·hr/mL, or about 2 ng·hr/mLto about 8 ng·hr/mL, or about 2 ng·hr/mL to about 7 ng·hr/mL, or about 2ng·hr/mL to about 6 ng·hr/mL, or about 2 ng·hr/mL to about 5 ng·hr/mL,or about 2 ng·hr/mL to about 4 ng·hr/mL, or about 1 ng·hr/mL to about 60ng·hr/mL, or about 1 ng·hr/mL to about 50 ng·hr/mL, or about 1 ng·hr/mLto about 40 ng·hr/mL, or about 3 ng·hr/mL to about 40 ng·hr/mL, or about4 ng·hr/mL to about 50 ng·hr/mL, or about 5 ng·hr/mL to about 30ng·hr/mL.

In some preferred embodiments, the dosage form provides an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for three times-a-day (Q8H or Q8H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a mean butorphanol AUC_(0-inf) after firstadministration or AUC₀₋₈ at steady state of not more than about 200ng·hr/mL; and said dosage form providing a therapeutic effect for atleast about 8 hours. In other preferred embodiments, the dosage formprovides a mean butorphanol AUC_(0-inf) after first administration orAUC₀₋₈ at steady state of not more than about 175 ng·hr/mL, or not morethan about 150 ng·hr/mL, or not more than about 125 ng·hr/mL, or notmore than about 100 ng·hr/mL, or not more than about 75 ng·hr/mL, or notmore than about 50 ng·hr/mL, or not more than about 40 ng·hr/mL, or notmore than about 30 ng·hr/mL, or not more than about 20 ng·hr/mL, or notmore than about 10 ng·hr/mL, or not more than about 5 ng·hr/mL.

In some preferred embodiments, the dosage form provides an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for three times-a-day (Q8H or Q8H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a mean butorphanol AUC_(0-inf) after firstadministration or AUC₀₋₈ at steady state of not less than about 200ng·hr/mL; and said dosage form providing a therapeutic effect for atleast about 8 hours. In other preferred embodiments, the dosage formprovides a mean butorphanol AUC_(0-inf) after first administration orAUC₀₋₈ at steady state of not less than about 30 ng·hr/mL, or not lessthan about 20 ng·hr/mL, or not less than about 10 ng·hr/mL, or not lessthan about 8 ng·hr/mL, or not less than about 6 ng·hr/mL, or not lessthan about 5 ng·hr/mL, or not less than about 4 ng·hr/mL, or not lessthan about 2 ng·hr/mL, or not less than about 1 ng·hr/mL.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol and controlled release material torender said dosage form suitable for three times-a-day (Q8H or Q8H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a C₈/C_(max) ratio of butorphanol 0.1 toabout 1.25; and said dosage form providing a therapeutic effect for atleast about 8 hours. In other preferred embodiments, the dosage formprovides a C₈/C_(max) ratio of butorphanol of about 0.1 to about 1, orabout 0.1 to about 0.8, or about 0.1 to about 0.75, or about 0.1 toabout 0.6, or 0.1 to about 0.5, or about 0.1 to about 0.4, or about 0.1to about 0.35, or about 0.25 to about 0.95, or about 0.4 to about 0.95,or about 0.5 to about 0.95, or about 0.65 to about 0.95, or about 0.75to about 0.95, or about 0.3 to about 0.8, or about 0.4 to about 0.75, orabout 0.5 to about 0.75. In some preferred embodiments, theaforementioned C₈/C_(max) ratio being achieved with oral pharmaceuticalcompositions devoid of a controlled release material to render saiddosage form extended release.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol and controlled release material torender said dosage form suitable for three times-a-day (Q8H or Q8H PRN)administration to a human patient, said dosage form after administrationto a human patient, providing a W₅₀ of butorphanol of 1 to about 7hours; and said dosage form providing a therapeutic effect for at leastabout 8 hours. In other preferred embodiments, the dosage form providesa W₅₀ of butorphanol of about 1 to about 6 hours, or about 1 to about 5hours, or about 1 to about 5.5 hours, or about 1 to about 5 hours, or 1to about 4.5 hours, or about 1 to about 4 hours, or about 1 to about 3.5hours, or about 1 to about 3 hours, or about 1 to about 2.5 hours, orabout 1 to about 2 hours, or about 1.5 to about 7 hours, or about 2 toabout 6 hours, or 2 to about 5.5 hours, or about 2 to about 5 hours, orabout 2 to about 4.5 hours, or about 2 to about 4 hours, or about 2 toabout 3.5 hours, or about 2.5 to about 6.5 hours, or about 2.5 to about6 hours, or about 2.5 to about 5 hours, or about 2.5 to about 4.5 hours,or 3 to about 6.5 hours, or about 3 to about 6 hours, or about 3 toabout 5 hours, or about 3 to about 6.5 hours. In some preferredembodiments, the aforementioned W₅₀ ratio being achieved with oralpharmaceutical compositions devoid of a controlled release material torender said dosage form extended release.

In some preferred embodiments, the dosage form comprises an oralmodified release pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol and controlled release material torender said dosage form suitable for three times-a-day (Q8H or Q8H PRN)administration to a human patient, said dosage form after administrationto a human patient, providing a HVD of butorphanol of 1.5 to about 7hours; and said dosage form providing a therapeutic effect for at leastabout 8 hours. In other preferred embodiments, the dosage form providesa HVD of butorphanol of about 1.5 to about 6 hours, or about 1.5 toabout 5 hours, or about 1.5 to about 5.5 hours, or about 1.5 to about 5hours, or 1.5 to about 4.5 hours, or about 1.5 to about 4 hours, orabout 1.5 to about 3.5 hours, or about 1.5 to about 3 hours, or about1.5 to about 2.5 hours, or about 1.5 to about 2 hours, or about 1.5 toabout 7 hours, or about 2 to about 6 hours, or 2 to about 5.5 hours, orabout 2 to about 5 hours, or about 2 to about 4.5 hours, or about 2 toabout 4 hours, or about 2 to about 3.5 hours, or about 2.5 to about 6.5hours, or about 2.5 to about 6 hours, or about 2.5 to about 5 hours, orabout 2.5 to about 4.5 hours, or 3 to about 6.5 hours, or about 3 toabout 6 hours, or about 3 to about 5 hours, or about 3 to about 6.5hours. In some preferred embodiments, the aforementioned HVD ratio beingachieved with oral pharmaceutical compositions devoid of a controlledrelease material to render said dosage form extended release.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and controlled release material to render said dosageform suitable for twice-a-day administration to a human patient, saiddosage form after administration to a human patient providing a C_(max)of butorphanol at 2 to about 10 hours; and said dosage form providing atherapeutic effect for at least about 12 hours. In other preferredembodiments, the dosage form provides a C_(max) of butorphanol at about2 to about 8 hour or about 2 to about 6 hours, or about 2 to about 5hours, or about 2 to about 7 hours, or about 2 to about 4.5 hours, orabout 2 to about 4 hours, or 2 to about 3.5 hours, or about 2 to about 3hours, or about 3 to about 10 hours, or about 3.5 to about 10 hours, orabout 4 to about 10 hours, or about 4.5 to about 10 hours, or about 5 toabout 10 hours, or 5 to about 10 hours, or about 6 to about 10 hours, orabout 3 to about 8 hours, or about 3 to about 7 hours, or about 3 toabout 6 hours, or about 4 to about 8 hours, or about 4 to about 6. Insome preferred embodiments, the aforementioned C_(max) being achievedwith oral pharmaceutical compositions devoid of a controlled releasematerial to render said dosage form extended release.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and controlled release material to render said dosageform suitable for twice-a-day administration to a human patient, saiddosage form after administration to a human patient providing a C_(min)of butorphanol at about 10 to about 14 hours; and said dosage formproviding a therapeutic effect for at least about 12 hours. In otherpreferred embodiments, the dosage form provides a C_(min) of butorphanolat about 10 to about 13 hours, or about 10 to about 12.5 hours, or about10 to about 12 hours, or about 10 to about 11.5 hours, or about 10 toabout 11 hours, or about 10.5 to about 14 hours, or about 11 to about 14hours, or about 12 to about 14 hours. In some preferred embodiments, theaforementioned C_(min) being achieved with oral pharmaceuticalcompositions devoid of a controlled release material to render saiddosage form extended release.

In some preferred embodiments, the dosage form provides an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for twice-a-day (Q12H or Q12H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a mean butorphanol AUC_(0-inf) after firstadministration or AUC₀₋₁₂ at steady state of about 2 ng·hr/mL to about300 ng·hr/mL; and said dosage form providing a therapeutic effect for atleast about 12 hours. In other preferred embodiments, the dosage formprovides a mean butorphanol AUC_(0-inf) after first administration orAUC₀₋₁₂ at steady state of about 2 ng·hr/mL to about 275 ng·hr/mL, orabout 2 ng·hr/mL to about 250 ng·hr/mL, or about 2 ng·hr/mL to about 225ng·hr/mL, about 2 ng·hr/mL to about 200 ng·hr/mL, or about 2 ng·hr/mL toabout 175 ng·hr/mL, or about 2 ng·hr/mL to about 150 ng·hr/mL, or about2 ng·hr/mL to about 125 ng·hr/mL, or about 2 ng·hr/mL to about 110ng·hr/mL, or about 2 ng·hr/mL to about 90 ng·hr/mL, or about 2 ng·hr/mLto about 8 ng·hr/mL, or about 2 ng·hr/mL to about 70 ng·hr/mL, or about2 ng·hr/mL to about 60 ng·hr/mL, or about 2 ng·hr/mL to about 50ng·hr/mL, or about 2 ng·hr/mL to about 45 ng·hr/mL, or about 2 ng·hr/mLto about 40 ng·hr/mL, or about 2 ng·hr/mL to about 35 ng·hr/mL, or about2 ng·hr/mL to about 30 ng·hr/mL, or about 2 ng·hr/mL to about 28ng·hr/mL, or about 2 ng·hr/mL to about 25 ng·hr/mL, or about 2 ng·hr/mLto about 22 ng·hr/mL, or about 2 ng·hr/mL to about 20 ng·hr/mL, or about2 ng·hr/mL to about 18 ng·hr/mL, or about 2 ng·hr/mL to about 16ng·hr/mL, or about 2 ng·hr/mL to about 15 ng·hr/mL, or about 2 ng·hr/mLto about 14 ng·hr/mL, or about 2 ng·hr/mL to about 12 ng·hr/mL, or about2 ng·hr/mL to about 10 ng·hr/mL, or about 2 ng·hr/mL to about 9ng·hr/mL, or about 2 ng·hr/mL to about 8 ng·hr/mL, or about 2 ng·hr/mLto about 7 ng·hr/mL, or about 2 ng·hr/mL to about 6 ng·hr/mL, or about 1ng·hr/mL to about 300 ng·hr/mL, or about 3 ng·hr/mL to about 300ng·hr/mL, or about 4 ng·hr/mL to about 300 ng·hr/mL, or about 5 ng·hr/mLto about 300 ng·hr/mL, or about 6 ng·hr/mL to about 300 ng·hr/mL, orabout 7 ng·hr/mL to about 300 ng·hr/mL, or about 8 ng·hr/mL to about 300ng·hr/mL, or about 9 ng·hr/mL to about 300 ng·hr/mL, or about 10ng·hr/mL to about 300 ng·hr/mL, or about 11 ng·hr/mL to about 300ng·hr/mL, or about 12 ng·hr/mL to about 300 ng·hr/mL, or about 14ng·hr/mL to about 300 ng·hr/mL, or about 15 ng·hr/mL to about 300ng·hr/mL, or about 1 ng·hr/mL to about 100 ng·hr/mL, or about 1 ng·hr/mLto about 50 ng·hr/mL, or about 3 ng·hr/mL to about 100 ng·hr/mL, orabout 4 ng·hr/mL to about 100 ng·hr/mL, or about 5 ng·hr/mL to about 100ng·hr/mL.

In some preferred embodiments, the dosage form provides an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for twice-a-day (Q12H or Q12H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a mean butorphanol AUC_(0-inf) after firstadministration or AUC₀₋₁₂ at steady state of not more than about 300ng·hr/mL; and said dosage form providing a therapeutic effect for atleast about 12 hours. In other preferred embodiments, the dosage formprovides a mean butorphanol AUC_(0-inf) after first administration orAUC₀₋₁₂ at steady state of not more than about 275 ng·hr/mL, or not morethan about 250 ng·hr/mL, or not more than about 225 ng·hr/mL, or notmore than about 200 ng·hr/mL, or not more than about 175 ng·hr/mL, ornot more than about 150 ng·hr/mL, or not more than about 125 ng·hr/mL,or not more than about 100 ng·hr/mL, or not more than about 75 ng·hr/mL,or not more than about 50 ng·hr/mL, or not more than about 40 ng·hr/mL,or not more than about 30 ng·hr/mL, or not more than about 20 ng·hr/mL,or not more than about 10 ng·hr/mL, or not more than about 5 ng·hr/mL.

In some preferred embodiments, the dosage form provides an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for twice-a-day (Q12H or Q12H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a mean butorphanol AUC_(0-inf) after firstadministration or AUC₀₋₁₂ at steady state of not less than about 300ng·hr/mL; and said dosage form providing a therapeutic effect for atleast about 12 hours. In other preferred embodiments, the dosage formprovides a mean butorphanol AUC_(0-inf) after first administration orAUC₀₋₁₂ at steady state of not less than about 275 ng·hr/mL, or not lessthan about 250 ng·hr/mL, or not less than about 225 ng·hr/mL, or notless than about 200 ng·hr/mL, or not less than about 175 ng·hr/mL, ornot less than about 150 ng·hr/mL, or not less than about 125 ng·hr/mL,or not less than about 100 ng·hr/mL, or not less than about 75 ng·hr/mL,or not less than about 50 ng·hr/mL, or not less than about 40 ng·hr/mL,or not less than about 30 ng·hr/mL, or not less than about 20 ng·hr/mL,or not less than about 10 ng·hr/mL, or not less than about 5 ng·hr/mL.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and controlled release material to render said dosageform suitable for twice-a-day administration to a human patient, saiddosage form after administration to a human patient providing aC₁₂/C_(max) ratio of butorphanol 0.1 to about 1.25; and said dosage formproviding a therapeutic effect for at least about 12 hours. In otherpreferred embodiments, the dosage form provides a C₁₂/C_(max) ratio ofbutorphanol of about 0.1 to about 1, or about 0.1 to about 0.8, or about0.1 to about 0.75, or about 0.1 to about 0.6, or 0.1 to about 0.5, orabout 0.1 to about 0.4, or about 0.1 to about 0.35, or about 0.25 toabout 0.95, or about 0.4 to about 0.95, or about 0.5 to about 0.95, orabout 0.65 to about 0.95, or about 0.75 to about 0.95, or about 0.3 toabout 0.8, or about 0.4 to about 0.75, or about 0.5 to about 0.75. Insome preferred embodiments, the aforementioned C₁₂/C_(max) ratio beingachieved with oral pharmaceutical compositions devoid of a controlledrelease material to render said dosage form extended release.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and, optionally, controlled release material to rendersaid dosage form suitable for twice-a-day administration to a humanpatient, said dosage form after administration to a human patient,providing a W₅₀ of butorphanol of 2 to about 11 hours; and said dosageform providing a therapeutic effect for at least about 12 hours. Inother preferred embodiments, the dosage form provides a W₅₀ ofbutorphanol of about 2 to about 10 hours, or about 2 to about 9 hours,or about 2 to about 9 hours, or about 2 to about 8 hours, or 2 to about7 hours, or about 2 to about 6 hours, or about 2 to about 5 hours, orabout 2 to about 4 hours, or about 3 to about 10 hours, or about 4 toabout 10 hours, or about 5 to about 10 hours, or about 6 to about 10hours, or 7 to about 10 hours, or about 3 to about 8 hours, or about 4to about 8 hours, or about 4 to about 7 hours, or about 3 to about 6hours.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and, optionally, controlled release material to rendersaid dosage form suitable for twice-a-day administration to a humanpatient, said dosage form after administration to a human patient,providing a HVD of butorphanol of 1.5 to about 10 hours; and said dosageform providing a therapeutic effect for at least about 12 hours. Inother preferred embodiments, the dosage form provides an HVD ofbutorphanol of about 1.5 to about 9 hours, or about 1.5 to 8 hours, orabout 1.5 to about 7 hours, or about 1.5 to 6 hours, or about 1.5 toabout 5 hours, or about 1.5 to about 4 hours, or about 2 to about 10hours, or about 3 to 10 hours, or about 4 to about 10 hours, or about 5to 10 hours, or about 6 to about 10 hours, or about 8 to 10 hours, about3 to about 8 hours, or about 4 to 8 hours, or about 5 to about 7 hours,or about 3 to 6 hours, or about 3 to about 8 hours, or about 5 to about8 hours.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and, optionally, controlled release material to rendersaid dosage form suitable for once-a-day administration to a humanpatient, said dosage form after administration to a human patientproviding a C_(max) of butorphanol at about 3 to about 20 hours; andsaid dosage form providing a therapeutic effect for at least about 24hours. In some preferred embodiments, the dosage form provides a C_(max)at about 3 to about 18 hours, or about 3 to about 15 hours, or about 3to about 12 hours, or at about 3 to about 10 hours, or at about 3 toabout 8 hours, or at about 3 to about 7 hours, or at about 3 to about 7hours, or about 4 to about 20 hours, or about 5 to about 20 hours, orabout 6 to about 20 hours, or at about 8 to about 20 hours, or at about10 to about 20 hours, or at about 12 to about 20 hours, or at about 14to about 20 hours, or about 18 to about 20 hours, or about 4 to about 18hours, or about 4 to about 16 hours, or at about 4 to about 12 hours, orat about 4 to about 8 hours, or at about 4 to about 10 hours, or atabout 3 to about 6 hours.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and, optionally, controlled release material to rendersaid dosage form suitable for once-a-day administration to a humanpatient, said dosage form after administration to a human patientproviding a C_(min) of butorphanol at about 20 to about 28 hours; andsaid dosage form providing a therapeutic effect for at least about 24hours. In some preferred embodiments, the dosage form provides a C_(min)at about 20 to about 26 hours, or about 20 to about 27 hours, or about20 to about 25 hours, or about 20 to about 24 hours, or about 20 toabout 23 hours, or about 21 to about 28 hours, or about 22 to about 28hours, or about 23 to about 28 hours, or about 23.5 to about 28 hours,or about 22 to 26 hours.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; said dosage form providing a therapeutic effect longerthan would be expected based on the prevailing plasma concentrations.For example, under normal circumstances, many drugs provide duration ofeffect that is at least partly correlated with or dependent on theprevailing plasma concentrations of drug. In some preferred embodimentsof the invention, the dosage form provides persistent therapeuticeffects despite short lived, low or negligible prevailing plasmaconcentrations.

In some preferred embodiments of the invention, the dosage form providessustained therapeutic effects of up to about 4, or about 6, or about 8,or about 12, or about 18 or about 20 or about 24 hours despite beingadministered in immediate release form.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; said dosage from providing a Cmax of butorphanol fromabout 0.25 hours to about 30 hours.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol; said dosage from providing a C_(min) of butorphanol fromabout 1 hour to about 30 hours.

In some preferred embodiments, the dosage form provides an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for once-a-day (Q24H OR Q24H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a butorphanol mean AUC_(0-inf) after firstadministration or AUC₀₋₂₄ at steady state of about 4 ng·hr/mL to about60 ng·hr/mL; and said dosage form providing a therapeutic effect for atleast about 24 hours. In other preferred embodiments, the dosage formprovides a mean butorphanol AUC_(0-inf) after first administration orAUC₀₋₂₄ at steady state of about 4 ng·hr/mL to about 550 ng·hr/mL, orabout 4 ng·hr/mL to about 500 ng·hr/mL, or about 4 ng·hr/mL to about 450ng·hr/mL, or about 4 ng·hr/mL to about 400 ng·hr/mL, or about 4 ng·hr/mLto about 375 ng·hr/mL, or about 4 ng·hr/mL to about 350 ng·hr/mL, orabout 4 ng·hr/mL to about 325 ng·hr/mL, or about 4 ng·hr/mL to about 300ng·hr/mL, or about 4 ng·hr/mL to about 275 ng·hr/mL, or about 4 ng·hr/mLto about 250 ng·hr/mL, or about 4 ng·hr/mL to about 225 ng·hr/mL, about4 ng·hr/mL to about 200 ng·hr/mL, or about 4 ng·hr/mL to about 175ng·hr/mL, or about 4 ng·hr/mL to about 150 ng·hr/mL, or about 4 ng·hr/mLto about 125 ng·hr/mL, or about 4 ng·hr/mL to about 110 ng·hr/mL, orabout 4 ng·hr/mL to about 90 ng·hr/mL, or about 4 ng·hr/mL to about 8ng·hr/mL, or about 4 ng·hr/mL to about 70 ng·hr/mL, or about 4 ng·hr/mLto about 60 ng·hr/mL, or about 4 ng·hr/mL to about 50 ng·hr/mL, or about4 ng·hr/mL to about 45 ng·hr/mL, or about 4 ng·hr/mL to about 40ng·hr/mL, or about 4 ng·hr/mL to about 35 ng·hr/mL, or about 4 ng·hr/mLto about 30 ng·hr/mL, or about 4 ng·hr/mL to about 28 ng·hr/mL, or about4 ng·hr/mL to about 25 ng·hr/mL, or about 4 ng·hr/mL to about 24ng·hr/mL, or about 4 ng·hr/mL to about 20 ng·hr/mL, or about 4 ng·hr/mLto about 18 ng·hr/mL, or about 4 ng·hr/mL to about 16 ng·hr/mL, or about4 ng·hr/mL to about 15 ng·hr/mL, or about 4 ng·hr/mL to about 14ng·hr/mL, or about 4 ng·hr/mL to about 14 ng·hr/mL, or about 4 ng·hr/mLto about 10 ng·hr/mL, or about 4 ng·hr/mL to about 9 ng·hr/mL, or about4 ng·hr/mL to about 8 ng·hr/mL, or about 4 ng·hr/mL to about 7 ng·hr/mL,or about 1 ng·hr/mL to about 600 ng·hr/mL, or about 3 ng·hr/mL to about600 ng·hr/mL, or about 4 ng·hr/mL to about 600 ng·hr/mL, or about 5ng·hr/mL to about 600 ng·hr/mL, or about 6 ng·hr/mL to about 600ng·hr/mL, or about 7 ng·hr/mL to about 600 ng·hr/mL, or about 10ng·hr/mL to about 600 ng·hr/mL, or about 12 ng·hr/mL to about 600ng·hr/mL, or about 15 ng·hr/mL to about 600 ng·hr/mL, or about 10ng·hr/mL to about 400 ng·hr/mL, or about 15 ng·hr/mL to about 300ng·hr/mL, or about 15 ng·hr/mL to about 200 ng·hr/mL, or about 15ng·hr/mL to about 100 ng·hr/mL, or about 1 ng·hr/mL to about 100ng·hr/mL, or about 1 ng·hr/mL to about 50 ng·hr/mL, or about 3 ng·hr/mLto about 100 ng·hr/mL, or about 4 ng·hr/mL to about 100 ng·hr/mL, orabout 5 ng·hr/mL to about 100 ng·hr/mL. In some preferred embodiments,the aforementioned AUC_(0-inf) being achieved with oral pharmaceuticalcompositions comprising a controlled release material to render saiddosage form suitable for extended release.

In some preferred embodiments, the dosage form provides an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for once-a-day (Q24H OR Q24H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a butorphanol mean AUC_(0-inf) after firstadministration or AUC₀₋₂₄ at steady state of not more than about 600ng·hr/mL; and said dosage form providing a therapeutic effect for atleast about 24 hours. In other preferred embodiments, the dosage formprovides a mean butorphanol AUC_(0-inf) after first administration orAUC₀₋₂₄ at steady state of not more than about 550 ng·hr/mL, or not morethan about 500 ng·hr/mL, or not more than about 450 ng·hr/mL, or notmore than about 400 ng·hr/mL, or not more than about 350 ng·hr/mL, ornot more than about 300 ng·hr/mL, or not more than about 275 ng·hr/mL,or not more than about 250 ng·hr/mL, or not more than about 225ng·hr/mL, or not more than about 200 ng·hr/mL, or not more than about175 ng·hr/mL, or not more than about 150 ng·hr/mL, or not more thanabout 125 ng·hr/mL, or not more than about 100 ng·hr/mL, or not morethan about 75 ng·hr/mL, or not more than about 50 ng·hr/mL, or not morethan about 40 ng·hr/mL, or not more than about 30 ng·hr/mL, or not morethan about 20 ng·hr/mL, or not more than about 10 ng·hr/mL, or not morethan about 5 ng·hr/mL.

In some preferred embodiments, the dosage form provides an oral modifiedrelease pharmaceutical composition comprising a therapeuticallyeffective amount of butorphanol or a pharmaceutically acceptable salt ofbutorphanol, or a mixture thereof and controlled release material torender said dosage form suitable for once-a-day (Q24H OR Q24H PRN)administration to a human patient, said dosage form after administrationto a human patient providing a butorphanol mean AUC_(0-inf) after firstadministration or AUC₀₋₂₄ at steady state of not less than about 600ng·hr/mL; and said dosage form providing a therapeutic effect for atleast about 24 hours. In other preferred embodiments, the dosage formprovides a mean butorphanol AUC_(0-inf) after first administration orAUC₀₋₂₄ at steady state of not less than about 550 ng·hr/mL, or not lessthan about 500 ng·hr/mL, or not less than about 450 ng·hr/mL, or notless than about 400 ng·hr/mL, or not less than about 350 ng·hr/mL, ornot less than about 300 ng·hr/mL, or not less than about 275 ng·hr/mL,or not less than about 250 ng·hr/mL, or not less than about 225ng·hr/mL, or not less than about 200 ng·hr/mL, or not less than about175 ng·hr/mL, or not less than about 150 ng·hr/mL, or not less thanabout 125 ng·hr/mL, or not less than about 100 ng·hr/mL, or not lessthan about 75 ng·hr/mL, or not less than about 50 ng·hr/mL, or not lessthan about 40 ng·hr/mL, or not less than about 30 ng·hr/mL, or not lessthan about 20 ng·hr/mL, or not less than about 10 ng·hr/mL, or not lessthan about 5 ng·hr/mL.

In some preferred embodiments, the oral dosage form of the inventionprovides at least about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or50% or 60%, or 70%, or 80%, or 100% lower variability in butorphanolC_(max) (as defined by the coefficient of variation or C.V.) than afterthe intranasal dosage form of butorphanol, each given according to itsintended route and method of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides at least about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or50% or 60%, or 70%, or 80%, or 100% lower variability in butorphanolT_(max) (as defined by the coefficient of variation or C.V.) than afterthe intranasal dosage form of butorphanol, each given according to itsintended route and method of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides at least about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or50% or 60%, or 70%, or 80%, or 100% lower variability in the butorphanolAUC₀₋₂₄, or AUC₀₋₃₆, or AUC₀₋₄₈, or AUC₀₋₇₂ (as defined by thecoefficient of variation or C.V.) than after the intranasal dosage formof butorphanol, each given according to its intended route and method ofadministration.

In some preferred embodiments, the oral dosage form of the inventionprovides a ratio of mean AUC₀₋₄₈ of hydroxybutorphanol to butorphanolafter the first dose which is at least about 5%, or 10%, or 15%, or 20%,or 30% or 40%, or 50% or 60%, or 70%, or 80%, or 100%, or 120%, or 140%,or 150%, or 170%, or 200%, or 230%, or 250%, or 270%, or 300% greaterthan said ratio after the same amount of intranasal dosage form ofbutorphanol, each given according to its intended route and method ofadministration.

In some preferred embodiments, the oral dosage form of the inventionprovides a time to 75% mean C_(max) of butorphanol after the first dosewhich is at least about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or50% or 60%, or 70%, or 80%, or 100%, or 120%, or 140%, or 150%, or 170%,or 200%, or 230%, or 250%, or 270%, or 300% or 400%, or 500%, or 600%,or 700%, or 1000% longer than said time to mean C_(max) after the sameamount of intranasal dosage form of butorphanol, each given according toits intended route and method of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean T_(max) of butorphanol after the first dose which is atleast about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or 50% or 60%, or70%, or 80%, or 100%, or 120%, or 140%, or 150%, or 170%, or 200%, or230%, or 250%, or 270%, or 300% or 400%, or 500%, or 600%, or 700%, or1000% longer than said T_(max) after the same amount of intranasaldosage form of butorphanol, each given according to its intended routeand method of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean C_(max) of butorphanol which is at least about 5%, or10%, or 15%, or 20%, or 30% or 40%, or 50% or 60%, or 70%, or 80%, or100%, or 120%, or 140%, or 150%, or 170%, or 200%, or 230%, or 250%, or270%, or 300% less than said C_(max) after the same amount of intranasaldosage form of butorphanol, each given according to its intended routeand method of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean C_(max) ratio of hydroxybutorphanol to butorphanol whichis at least about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or 50% or60%, or 70%, or 80%, or 100%, or 120%, or 140%, or 150%, or 170%, or200%, or 230%, or 250%, or 270%, or 300% greater than said C_(max) ratioafter the same amount of intranasal dosage form of butorphanol, eachgiven according to its intended route and method of administration.

In some preferred embodiments, a controlled release dosage form of theinvention provides a time to mean C_(max) of butorphanol which is atleast about 1.25, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 12 fold greaterthan the time to mean C_(max) after the same amount of an oral immediaterelease butorphanol solution.

In some preferred embodiments, the oral dosage form of the inventionprovides a time to mean C_(max) of butorphanol which is at least about1.25, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 12 fold greater than the timeto mean C_(max) after the same amount of an intranasal formulation ofbutorphanol or an immediate release dosage form given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean C_(max) of butorphanol which is at least about 5%, 10%,15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%,180%, 200%, 230%, 260%, or 300% lower than the mean C_(max) after thesame amount of an intranasal formulation of butorphanol or an immediaterelease dosage form given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a ratio of mean AUC₀₋₁₄ of hydroxybutorphanol to butorphanolafter the first dose which is at least about 5%, 10%, 15%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%,260%, or 300% greater than the said ratio after the same amount of anintranasal formulation of butorphanol, each given according to itsintended route of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides a ratio of mean AUC₀₋₂₄ of hydroxybutorphanol to butorphanolafter the first dose which is at least about 5%, 10%, 15%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%,260%, or 300% greater than the said ratio after the same amount of anintranasal formulation of butorphanol, each given according to itsintended route of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides a ratio of mean AUC₀₋₃₆ of hydroxybutorphanol to butorphanolafter the first dose which is at least about 5%, 10%, 15%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%,260%, or 300% greater than the said ratio after the same amount of anintranasal formulation of butorphanol, each given according to itsintended route of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides a ratio of mean AUC₀₋₄₈ of hydroxybutorphanol to butorphanolafter the first dose which is at least about 5%, 10%, 15%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%,260%, or 300% greater than the said ratio after the same amount of anintranasal formulation of butorphanol, each given according to itsintended route of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides a ratio of mean AUC₀₋₆₀ of hydroxybutorphanol to butorphanolafter the first dose which is at least about 5%, 10%, 15%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%,260%, or 300% greater than the said ratio after the same amount of anintranasal formulation of butorphanol, each given according to itsintended route of administration.

In some preferred embodiments, the oral immediate release and oralextended release dosage forms provide a ratio of mean AUC₀₋₁₂, orAUC₀₋₂₄, or AUC₀₋₄₈ of hydroxybutorphanol to butorphanol after the firstdose which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300%greater than the said ratio after intranasal butorphanol, each givenaccording to its intended route and method of administration.

In some preferred embodiments, the oral immediate release and oralextended release dosage forms provides a ratio of mean AUC₀₋₂₄, orAUC₀₋₃₆, or AUC₀₋₄₈, or AUC₀₋₇₂ of hydroxybutorphanol to butorphanolafter the first dose which is at least about 5%, 10%, 15%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%,260%, or 300% greater than the said ratio after a intranasal formulationof butorphanol, each given according to its intended route and method ofadministration.

In some preferred embodiments, the oral extended release dosage formprovides a ratio of mean AUC₀₋₂₄, or AUC₀₋₃₆, or AUC₀₋₄₈, or AUC₀₋₇₂ ofhydroxybutorphanol to butorphanol after the first dose which is at leastabout 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%,140%, 150%, 180%, 200%, 230%, 260%, or 300% less than the said ratioafter the same amount of an oral immediate release formulation ofbutorphanol.

In some preferred embodiments, the oral extended release dosage formprovides a mean extent of absorption (as measured by AUC₀₋₂₄, orAUC₀₋₃₆, or AUC₀₋₄₈, or AUC₀₋₇₂) of butorphanol after the first dosewhich is at least about 5%, 10%, 15%, 20%, 30%, or 40% greater than thesaid ratio after the same amount of an oral immediate releaseformulation of butorphanol.

In some preferred embodiments, the ratio of the mean ratio of the extentof absorption (as measured by AUC₀₋₂₄, or AUC₀₋₃₆, or AUC₀₋₄₈, orAUC₀₋₇₂) of hydroxybutorphanol to butorphanol oral extended releasebutorphanol after the first dose is at least about 5%, 10%, 15%, 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%,230%, 260%, or 300% less than the said ratio after the first dose of thesame amount of an oral immediate release formulation of butorphanol.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean drowsiness score in butorphanol and opioid naïvesubjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300%lower than the mean drowsiness score after the same amount of anintranasal formulation of butorphanol or an immediate release dosageform given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean dizziness score in butorphanol and opioid naïve subjectswhich is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower thanthe mean drowsiness score after the same amount of an intranasalformulation of butorphanol or an immediate release dosage form givenorally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean nausea score which is at least about 5%, 10%, 15%, 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%,230%, 260%, or 300% lower than the mean nausea score after the sameamount of an intranasal formulation of butorphanol or an immediaterelease dosage form given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean dizziness score in butorphanol and opioid naïve subjectswhich is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower thanthe mean vomiting score after the same amount of an intranasalformulation of butorphanol or an immediate release dosage form givenorally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean driving simulation impairment score in butorphanol andopioid naïve subjects which is at least about 5%, 10%, 15%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%,260%, or 300% lower than the mean driving simulation impairment scoreafter the same amount of an intranasal formulation of butorphanol or animmediate release dosage form given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean number needed to harm (NNH) due to moderate to severesedation or drowsiness in opioid naïve subjects which is at least about5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%,150%, 180%, 200%, 230%, 260%, or 300% lower than said score after anequal amount (or dose) or lower amount (or dose) of intranasalformulation of butorphanol or an immediate release dosage form givenorally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean number needed to harm (NNH) due to moderate or severenausea in opioid naïve subjects which is at least about 5%, 10%, 15%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%,200%, 230%, 260%, or 300% lower than said score after an equal amount(or dose) or lower amount (or dose) of intranasal formulation ofbutorphanol or an immediate release dosage form given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean number needed to harm (NNH) due to dizziness in opioidnaïve subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or300% lower than said score after an equal amount (or dose) or loweramount (or dose) of intranasal formulation of butorphanol or animmediate release dosage form given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean “drug effects” score in opioid abusers or recreationalopioid users which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or300% lower than said score after an equal amount (or dose) or loweramount (or dose) of intranasal formulation of butorphanol or animmediate release dosage form given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean “drug liking” score in opioid abusers or recreationalopioid users which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or300% lower than said score after an equal amount (or dose) or loweramount (or dose) of intranasal formulation of butorphanol or animmediate release dosage form given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean “take again” score in opioid abusers or recreationalopioid users which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or300% lower than said score after an equal amount (or dose) or loweramount (or dose) of intranasal formulation of butorphanol or animmediate release dosage form given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean “coasting” score in opioid abusers or recreationalopioid users which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or300% lower than said score after an equal amount (or dose) or loweramount (or dose) of intranasal formulation of butorphanol or animmediate release dosage form given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean “critical tracking task” impairment score in opioidnaïve subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or300% lower than said score after an equal amount (or dose) or loweramount (or dose) of intranasal formulation of butorphanol or animmediate release dosage form given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean “stop signal task” impairment score in opioid naïvesubjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300%lower than said score after an equal amount (or dose) or lower amount(or dose) of intranasal formulation of butorphanol or an immediaterelease dosage form given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean “Tower of London” (TOL) impairment score in opioid naïvesubjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300%lower than said score after an equal amount (or dose) or lower amount(or dose) of intranasal formulation of butorphanol or an immediaterelease dosage form given orally.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean ratio of street price at about 1, or 2, or 3, or 4 or 5,or 6 hours post-dose, after administration of an equal amount or dose ofintranasal formulation of butorphanol or an immediate release dosageform given orally to the dosage form of the invention is ≧1.10, ≧1.15,or ≧1.25, or ≧1.5, or ≧1.75, or ≧2, or ≧2.5, or ≧3, or ≧3.5, or ≧4, or≧4.5, or ≧5, or ≧5.5, or ≧6, or ≧6.5, or ≧7, or ≧7.5, or ≧8, or ≧8.5, or≧9, or ≧9.5, or ≧10, where “street price” is based the pricerecreational drug users or drug addicts would be prepared to pay afterconsuming said butorphanol by the intended method of use or by anymethod of use.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean ratio of street price at about 1, or 2, or 3, or 4 or 5,or 6 hours post-dose, after administration of an equal amount or dose ofintranasal formulation of butorphanol or an immediate release dosageform given orally to the dosage form of the invention is ≧1.10, ≧1.15,or ≧1.25, or ≧1.5, or ≧1.75, or ≧2, or ≧2.5, or ≧3, or ≧3.5, or ≧4, or≧4.5, or ≧5, or ≧5.5, or ≧6, or ≧6.5, or ≧7, or ≧7.5, or ≧8, or ≧8.5, or≧9, or ≧9.5, or ≧10, where “street price” is based the pricerecreational drug users or drug addicts would be prepared to pay afterconsuming said butorphanol by the intended method of use or by anymethod of use, and where said butorphanol use is followed about 0.5 to1.5 hours later by alcohol (ethanol) administration sufficient tomaintain a blood alcohol concentration of 0.04% to 0.08%.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean drowsiness score in opioid naïveor opioid inexperienced subjects which is at least about 5%, 10%, 15%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%,200%, 230%, 260%, or 300% lower than the mean drowsiness score after anequal amount (or dose) or lower amount (or dose) of an oral extendedrelease dosage form of butorphanol which is not delayed onset, extendedrelease.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean nausea score in opioid naïve oropioid inexperienced subjects which is at least about 5%, 10%, 15%, 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%,230%, 260%, or 300% lower than the mean nausea score after an equalamount (or dose) or lower amount (or dose) of an oral extended releasedosage form of butorphanol which is not delayed onset, extended release.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean driving simulation impairmentscore in opioid naïve or opioid inexperienced subjects which is at leastabout 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%,140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than the mean drivingsimulation impairment score after an equal amount (or dose) or loweramount (or dose) of an oral extended release dosage form of butorphanolwhich is not delayed onset, extended release.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean “drug effects” score in opioidabusers or recreational opioid users which is at least about 5%, 10%,15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%,180%, 200%, 230%, 260%, or 300% lower than said score after an equalamount (or dose) or lower amount (or dose) of an oral extended releasedosage form of butorphanol which is not delayed onset, extended release.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean “drug liking” score in opioidabusers or recreational opioid users which is at least about 5%, 10%,15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%,180%, 200%, 230%, 260%, or 300% lower than said score after an equalamount (or dose) or lower amount (or dose) of an oral extended releasedosage form of butorphanol which is not delayed onset, extended release.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean “take again” score in opioidabusers or recreational opioid users which is at least about 5%, 10%,15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%,180%, 200%, 230%, 260%, or 300% lower than said score after an equalamount (or dose) or lower amount (or dose) of an oral extended releasedosage form of butorphanol which is not delayed onset, extended release.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean “coasting” score in opioidabusers or recreational opioid users which is at least about 5%, 10%,15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%,180%, 200%, 230%, 260%, or 300% lower than said score after an equalamount (or dose) or lower amount (or dose) of an oral extended releasedosage form of butorphanol which is not delayed onset, extended release.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean “critical tracking task”impairment score in opioid naïve or opioid inexperienced subjects whichis at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than saidscore after an equal amount (or dose) or lower amount (or dose) of anoral extended release dosage form of butorphanol which is not delayedonset, extended release.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean “stop signal task” impairmentscore in opioid naïve or opioid inexperienced subjects which is at leastabout 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%,140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score afteran equal amount (or dose) or lower amount (or dose) of an oral extendedrelease dosage form of butorphanol which is not delayed onset, extendedrelease.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean “Tower of London” (TOL)impairment score in opioid naïve or opioid inexperienced subjects whichis at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than saidscore after an equal amount (or dose) or lower amount (or dose) of anoral extended release dosage form of butorphanol which is not delayedonset, extended release.

In some preferred embodiments, the ratio of the foregoing mean scoresfor drowsiness, dizziness score, nausea, driving simulation impairment,“drug effects”, “drug liking”, “take again”, “coasting”, “criticaltracking task” impairment, “stop signal task” impairment and “Tower ofLondon” (TOL) impairment after extended release dosage form ofbutorphanol given orally, to the delayed onset, extended releasebutorphanol dosage form, is at least about 10:1, or 8:1, or 6:1, or 5:1,or 4:1, or 3:1, or 2.5:1, or 2:1, or 1.75:1, or 1.5:1, or 1.25:1, or1.15:1, wherein the extended release dosage form is given at an equalamount or lower amount.

In some preferred embodiments, the foregoing mean scores for drowsiness,dizziness score, nausea, driving simulation impairment, “drug effects”,“drug liking”, “take again”, “coasting”, “critical tracking task”impairment, “stop signal task” impairment and “Tower of London” (TOL)impairment are measured after single administration or firstadministration. In some other preferred embodiments, the foregoing meanscores for drowsiness, dizziness score, nausea, driving simulationimpairment, “drug effects”, “drug liking”, “take again”, “coasting”,“critical tracking task” impairment, “stop signal task” impairment and“Tower of London” (TOL) impairment are measured after repeated doseadministration. In some preferred embodiments, the foregoing mean scoresfor drowsiness, dizziness score, nausea, driving simulation impairment,“drug effects”, “drug liking”, “take again”, “coasting”, “criticaltracking task” impairment, “stop signal task” impairment and “Tower ofLondon” (TOL) impairment are measured after administration to patientsin need of treatment with butorphanol. Most preferably, the foregoingmean scores for drowsiness, dizziness score, nausea, driving simulationimpairment, “drug effects”, “drug liking”, “take again”, “coasting”,“critical tracking task” impairment, “stop signal task” impairment and“Tower of London” (TOL) impairment are measured after firstadministration to opioid naïve subjects, between 0.5 to 6 hours afteradministration of the dosage form.

In some preferred embodiments, the foregoing drowsiness, dizzinessscore, nausea, driving simulation impairment, “drug effects”, “drugliking”, “take again”, “coasting”, “critical tracking task” impairment,“stop signal task” impairment and “Tower of London” (TOL) impairment isassessed at a time 2.5 to 6 hours after administration of the dosageform, following alcohol (ethanol) administration sufficient to maintaina blood alcohol concentration of 0.04% to 0.08%, said ethanoladministration 1.5 hours after said dosage form administration, saidsubjects only occasional or light consumers of alcohol.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean number needed to harm (NNH) dueto drowsiness in opioid naïve or opioid inexperienced subjects which isat least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than saidscore after an equal amount (or dose) or lower amount (or dose) of anoral extended release dosage form of butorphanol which is not delayedonset, extended release.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean number needed to harm (NNH) dueto moderate to severe nausea in opioid naïve or opioid inexperiencedsubjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300%lower than said score after an equal amount (or dose) or lower amount(or dose) of an oral extended release dosage form of butorphanol whichis not delayed onset, extended release.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean number needed to harm (NNH) dueto dizziness in opioid naïve or opioid inexperienced subjects which isat least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than saidscore after an equal amount (or dose) or lower amount (or dose) of anoral extended release dosage form of butorphanol which is not delayedonset, extended release.

In some preferred embodiments, the ratio of the foregoing NNH fordrowsiness, nausea and dizziness after extended release dosage form ofbutorphanol given orally, to the delayed onset, extended releasebutorphanol dosage form, is at least about 10:1, or 8:1, or 6:1, or 5:1,or 4:1, or 3:1, or 2.5:1, or 2:1, or 1.75:1, or 1.5:1, or 1.25:1, or1.15:1, wherein the extended release dosage form is given at an equalamount or lower amount.

In some preferred embodiments, the foregoing NNH for drowsiness, nauseaand dizziness is assessed at a time 2.5 to 6 hours after administrationof the dosage form, following alcohol (ethanol) administrationsufficient to maintain a blood alcohol concentration of 0.04% to 0.08%,said ethanol administration 1.5 hours after said dosage formadministration, said subjects only occasional or light consumers ofalcohol.

In some preferred embodiments, the foregoing NNH for drowsiness, nauseaand dizziness are measured after single administration or firstadministration. In some other preferred embodiments, the foregoing NNHfor drowsiness, nausea and dizziness are measured after repeated doseadministration. In some preferred embodiments, the foregoing NNH fordrowsiness, nausea and dizziness are measured after administration topatients in need of treatment with butorphanol. Most preferably, theforegoing NNH for drowsiness, nausea and dizziness are measured afterfirst administration to opioid naïve subjects, between 0.5 to 6 hoursafter administration of the dosage form.

As used herein, the phrase “after an equal amount or lower amount of animmediate release dosage form of butorphanol given orally” means anamount of oral immediate release butorphanol which is the equal to or atleast up to about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,60%, 65%, 70%, 75% or 80% less than the dose or amount of extendedrelease butorphanol in the dosage form of the invention, when saidamounts are expressed in mass units of unsalified butorphanol.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean ratio of street price at about1, or 2, or 3, or 4 or 5, or 6 hours post-dose, after administration ofan equal amount of an oral extended release dosage form of butorphanolwhich is not delayed onset, extended release to the dosage form of theinvention is ≧1.10, ≧1.15, or ≧1.25, or ≧1.5, or ≧1.75, or ≧2, or ≧2.5,or ≧3, or ≧3.5, or ≧4, or ≧4.5, or ≧5, or ≧5.5, or ≧6, or ≧6.5, or ≧7,or ≧7.5, or ≧8, or ≧8.5, or ≧9, or ≧9.5, or ≧10, where “street price” isbased the price recreational drug users or drug addicts would beprepared to pay after consuming said butorphanol by the intended methodof use or by any method of use.

In some preferred embodiments, the delayed onset, extended releasebutorphanol dosage form provides a mean ratio of street price at about1, or 2, or 3, or 4 or 5, or 6 hours post-dose, after administration ofan equal amount of an oral immediate release dosage form or an oralextended release dosage form of butorphanol which is not delayed onset,extended release to the dosage form of the invention is ≧1.10, ≧1.15, or≧1.25, or ≧1.5, or ≧1.75, or ≧2, or ≧2.5, or ≧3, or ≧3.5, or ≧4, or≧4.5, or ≧5, or ≧5.5, or ≧6, or ≧6.5, or ≧7, or ≧7.5, or ≧8, or ≧8.5, or≧9, or ≧9.5, or ≧10, where “street price” is based the pricerecreational drug users or drug addicts would be prepared to pay afterconsuming said butorphanol by the intended method of use or by anymethod of use, and where said butorphanol use is followed about 0.5 to1.5 hours later by alcohol (ethanol) administration sufficient tomaintain a blood alcohol concentration of 0.04% to 0.08%.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean C_(max) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with intranasal butorphanol, eachgiven to according to its intended route of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean C_(max) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with other available butorphanoldosage forms.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean C_(max) under single-dose fasted testconditions in healthy subjects which is statistically significantlydifferent, when compared with intranasal butorphanol, each given toaccording to its intended route of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean C_(max) under single-dose fasted testconditions in healthy subjects which is statistically significantlydifferent, when compared with oral ingestion of a conventional solution,suspension, immediate release tablet or capsule.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean C_(max) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with intranasal dosage forms ofbutorphanol dosage forms.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean C_(max) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with immediate release oralbutorphanol.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean C_(max) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with immediate release oralbutorphanol solution.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC₀₋₆, or AUC₀₋₈, or AUC₀₋₁₂, or AUC₀₋₂₄, orAUC_(0-τ), or AUC_(0-inf), under single-dose fasted test conditions inhealthy subjects which is statistically significantly different, whencompared with intranasal butorphanol, each given to according to itsintended route of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC₀₋₆, or AUC₀₋₈, or AUC₀₋₁₂, or AUC₀₋₂₄, orAUC_(0-τ), or AUC_(0-inf), under single-dose fasted test conditions inhealthy subjects which is statistically significantly different, whencompared with oral ingestion of a conventional solution, suspension,immediate release tablet or capsule.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC_(0-τ) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with intranasal butorphanol.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC_(0-τ) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with intranasal butorphanol, eachgiven to according to its intended route of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC_(0-τ) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with other available butorphanoldosage forms.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC_(0-τ) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with intranasal dosage forms ofbutorphanol dosage forms.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC_(0-τ) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with immediate release oralbutorphanol.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC_(0-τ) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with immediate release oralbutorphanol solution.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC_(0-inf) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with intranasal butorphanol.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC_(0-inf) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with intranasal butorphanol, eachgiven to according to its intended route of administration.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC_(0-inf) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with other available butorphanoldosage forms.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC_(0-inf) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with intranasal dosage forms ofbutorphanol dosage forms.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC_(0-inf) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with immediate release oralbutorphanol.

In some preferred embodiments, the oral dosage form of the inventionprovides a relative mean AUC_(0-inf) whose 90% confidence interval isoutside the 80.00% to 125.00, under single-dose fasted test conditionsin healthy subjects, when compared with immediate release oralbutorphanol solution.

In some preferred embodiments, the dosage from maintains a plasmabutorphanol concentration within 50% of C_(max) for about 1 to about 9hours, or about 2 to about 9 hours, or about 3 to about 9 hours, orabout 4 to about 9 hours, or about 5 to about 9 hours, or about 6 toabout 9 hours, or about 1 to about 8 hours, or about 2 to about 8 hours,or about 3 to about 8 hours, or about 4 to about 8 hours, or about 5 toabout 8 hours, or about 6 to about 8 hours, or about 2 to about 7 hours,or about 2 to about 6 hours, or about 2 to about 5 hours, or about 2 toabout 4 hours, or about 1 to about 4 hours, or about 1 to about 3 hours,or about 2 to about 6 hours, or about 3 to about 5 hours.

In some preferred embodiments, the dosage from maintains a plasmabutorphanol concentration within 50% of C_(max) for about 1 to about 9hours, or about 2 to about 9 hours, or about 3 to about 9 hours, orabout 4 to about 9 hours, or about 5 to about 9 hours, or about 6 toabout 9 hours, or about 1 to about 8 hours, or about 2 to about 8 hours,or about 3 to about 8 hours, or about 4 to about 8 hours, or about 5 toabout 8 hours, or about 6 to about 8 hours, or about 2 to about 7 hours,or about 2 to about 6 hours, or about 2 to about 5 hours, or about 2 toabout 4 hours, or about 1 to about 4 hours, or about 1 to about 3 hours,or about 2 to about 6 hours, or about 3 to about 5 hours during a 12hour dosing interval.

In some preferred embodiments, the dosage from maintains a plasmabutorphanol concentration within 50% of C_(max) for about 1 to about 20hours, or about 1 to about 18 hours or about 1 to about 16 hours, orabout 1 to about 14 hours or about 1 to about 10 hours, or about 1 toabout 8 hours or about 1 to about 6 hours, or about 1 to about 5 hoursor about 2 to about 20 hours, or about 4 to about 20 hours or about 4 toabout 18 hours, or about 5 to about 18 hours or about 6 to about 18hours, or about 7 to about 18 hours or about 8 to about 18 hours, orabout 10 to about 18 hours or about 12 to about 18 hours, or about 14 toabout 18 hours or about 4 to about 16 hours, or about 4 to about 12hours or about 4 to about 10 hours, or about 4 to about 8 hours or about5 to about 15 hours, or about 5 to about 10 hours or about 6 to about 18hours, or about 6 to about 12 hours or about 6 to about 10 hours, orabout 8 to about 18 hours or about 8 to about 16 hours, or about 10 toabout 18 hours.

In some preferred embodiments, the dosage from maintains a plasmabutorphanol concentration within 50% of C_(max) for about 1 to about 20hours, or about 1 to about 18 hours or about 1 to about 16 hours, orabout 1 to about 14 hours or about 1 to about 10 hours, or about 1 toabout 8 hours or about 1 to about 6 hours, or about 1 to about 5 hoursor about 2 to about 20 hours, or about 4 to about 20 hours or about 4 toabout 18 hours, or about 5 to about 18 hours or about 6 to about 18hours, or about 7 to about 18 hours or about 8 to about 18 hours, orabout 10 to about 18 hours or about 12 to about 18 hours, or about 14 toabout 18 hours or about 4 to about 16 hours, or about 4 to about 12hours or about 4 to about 10 hours, or about 4 to about 8 hours or about5 to about 15 hours, or about 5 to about 10 hours or about 6 to about 18hours, or about 6 to about 12 hours or about 6 to about 10 hours, orabout 8 to about 18 hours or about 8 to about 16 hours, or about 10 toabout 18 hours, during a 24 hour dosing interval.

In some preferred embodiments, the oral pharmaceutical composition ofbutorphanol or a pharmaceutically dosage from provides a butorphanolT_(max) greater than about 0.25 hours, or greater than about 0.5 hours,or greater than about 0.75 hours, or greater than about 1 hour, orgreater than about 1.5 hours, or greater than about 2 hours, or greaterthan about 2.5 hours, or greater than about 3 hours, or greater thanabout 3.5 hours, or greater than about 4 hours, or greater than about4.5 hours, or greater than about 5 hours, or greater than about 6 hours,or greater than about 8 hours, or greater than about 10 hours, orgreater than about 12 hours, or greater than about 14 hours, or greaterthan about 16 hours, or greater than about 17 hours, or greater thanabout 18 hours, or greater than about 20 hours, or greater than about 22hours, or greater than about 24 hours.

In some preferred embodiments, the oral pharmaceutical composition ofbutorphanol or a pharmaceutically dosage from provides a butorphanolT_(max) of about 0.25 to about 8 hours, about 0.5 to about 30 hours, orabout 0.5 to about 26 hours, or about 0.5 to about 22 hours, or about0.5 to about 20 hours, or about 0.5 to about 18 hours, or about 0.5 toabout 16 hours, or about 0.5 to about 14 hours, or about 0.5 to about 12hours, or about 0.5 to about 10 hours, or about 0.5 to about 9 hours, orabout 0.5 to about 8 hours, or about 0.5 to about 7 hours, or about 0.5to about 6 hours, or about 0.5 to about 5 hours, or about 0.5 to about 4hours, or about 0.5 to about 3 hours, or about 0.5 to about 2 hours, orabout 0.5 to about 1 hour, or about 1 to about 30 hours, or about 2 toabout 30 hours, or about 3 to about 30 hours, or about 4 to about 30hours, or about 5 to about 30 hours, or about 6 to about 30 hours, orabout 1 to about 24 hours, or about 2 to about 24 hours, or about 3 toabout 24 hours, or about 4 to about 24 hours, or about 5 to about 24hours, or about 6 to about 24 hours, or about 8 to about 24 hours, orabout 10 to about 24 hours, or about 12 to about 24 hours, or about 14to about 24 hours, or about 1.5 to about 16 hours, or about 2 to about16 hours, or about 2.5 to about 16 hours, or about 3 to about 16 hours,or about 3.5 to about 16 hours, or about 4 to about 16 hours, or about 5to about 16 hours, or about 6 to about 16 hours, or about 7 to about 16hours, or about 8 to about 16 hours, or about 10 to about 16 hours, orabout 12 to about 16 hours, or about 2 to about 10 hours, or about 2.5to about 10 hours, or about 3 to about 10 hours, or about 3.5 to about10 hours, or about 4 to about 10 hours, or about 4.5 to about 10 hours,or about 5 to about 10 hours, or about 6 to about 10 hours, or about 7to about 10 hours, or about 7.5 to about 10 hours.

In some preferred embodiments, the oral pharmaceutical composition ofbutorphanol or a pharmaceutically dosage from provides ahydroxybutorphanol T_(max) greater than about 0.25 hours, or greaterthan about 0.5 hours, or greater than about 0.75 hours, or greater thanabout 1 hour, or greater than about 1.5 hours, or greater than about 2hours, or greater than about 2.5 hours, or greater than about 3 hours,or greater than about 3.5 hours, or greater than about 4 hours, orgreater than about 4.5 hours, or greater than about 5 hours, or greaterthan about 6 hours, or greater than about 8 hours, or greater than about10 hours, or greater than about 12 hours, or greater than about 14hours, or greater than about 16 hours, or greater than about 17 hours,or greater than about 18 hours, or greater than about 20 hours, orgreater than about 22 hours, or greater than about 24 hours.

In some preferred embodiments, the oral pharmaceutical composition ofbutorphanol or a pharmaceutically dosage from provides ahydroxybutorphanol T_(max) of about 0.25 to about 8 hours, about 0.5 toabout 30 hours, or about 0.5 to about 26 hours, or about 0.5 to about 22hours, or about 0.5 to about 20 hours, or about 0.5 to about 18 hours,or about 0.5 to about 16 hours, or about 0.5 to about 14 hours, or about0.5 to about 12 hours, or about 0.5 to about 10 hours, or about 0.5 toabout 9 hours, or about 0.5 to about 8 hours, or about 0.5 to about 7hours, or about 0.5 to about 6 hours, or about 0.5 to about 5 hours, orabout 0.5 to about 4 hours, or about 0.5 to about 3 hours, or about 0.5to about 2 hours, or about 0.5 to about 1 hour, or about 1 to about 30hours, or about 2 to about 30 hours, or about 3 to about 30 hours, orabout 4 to about 30 hours, or about 5 to about 30 hours, or about 6 toabout 30 hours, or about 1 to about 24 hours, or about 2 to about 24hours, or about 3 to about 24 hours, or about 4 to about 24 hours, orabout 5 to about 24 hours, or about 6 to about 24 hours, or about 8 toabout 24 hours, or about 10 to about 24 hours, or about 12 to about 24hours, or about 14 to about 24 hours, or about 1.5 to about 16 hours, orabout 2 to about 16 hours, or about 2.5 to about 16 hours, or about 3 toabout 16 hours, or about 3.5 to about 16 hours, or about 4 to about 16hours, or about 5 to about 16 hours, or about 6 to about 16 hours, orabout 7 to about 16 hours, or about 8 to about 16 hours, or about 10 toabout 16 hours, or about 12 to about 16 hours, or about 2 to about 10hours, or about 2.5 to about 10 hours, or about 3 to about 10 hours, orabout 3.5 to about 10 hours, or about 4 to about 10 hours, or about 4.5to about 10 hours, or about 5 to about 10 hours, or about 6 to about 10hours, or about 7 to about 10 hours, or about 7.5 to about 10 hours.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean in vivo extent of absorption of butorphanol from 0 to 4hours which is at least 20% of the mean in vivo extent of absorptionfrom to 0 to 12 hours, wherein the mean in vivo extent of absorption isthe area under the plasma or serum butorphanol concentration time curvefrom the time of drug administration to the specified time point.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean in vivo extent of absorption of butorphanol from 0 to 8hours which is at least 20% of the mean in vivo extent of absorptionfrom to 0 to 24 hours, wherein the mean in vivo extent of absorption isthe area under the plasma or serum butorphanol concentration time curvefrom the time of drug administration to the specified time point.

In some preferred embodiments, the oral dosage form of the inventionprovides a mean in vivo extent of absorption of butorphanol over thedosing interval (e.g., from 0 to 12 hours or from 0 to 24 hours) whichis at least 40% of the mean in vivo extent of absorption from to 0 toinfinity, wherein the mean in vivo extent of absorption is the areaunder the plasma or serum butorphanol concentration time curves (AUC)from the time of drug administration to the specified time point andwhere AUC infinity is the sum of AUC from time “0” to time “t” (the lastquantifiable time point which has been sampled) plus the extrapolatedAUC from the last quantifiable sampling time point to infinity.

In some preferred embodiments, the oral butorphanol dosage form providesa mean in vivo extent of absorption of butorphanol from about 0 to about2 hours, or about 0 to about 3 hours, or about 0 to about 4 hours, orabout 0 to about 5 hours, or about 0 to about 6 hours, which is ≦about1% of the mean in vivo extent of absorption from to 0 to 12 hours,wherein the mean in vivo extent of absorption is the area under theplasma or serum butorphanol concentration time curve from the time ofdrug administration to the specified time point. In other embodiments,said in vivo extent of absorption from about 0 to about 2 hours, orabout 0 to about 3 hours, or about 0 to about 4 hours, or about 0 toabout 5 hours, or about 0 to about 6 hours is ≦about 2%, or ≦about 3%,or ≦about 4%, or ≦about 5%, or ≦about 6%, or ≦about 7%, or ≦about 8%, or≦about 9%, or ≦about 10%, or ≦about 12%, or ≦about 14%, or ≦about 15%,or ≦about 16%, or ≦about 18%, or ≦about 20%, or ≦about 25%, or ≦about30%, or ≦about 35% of the mean in vivo extent of absorption from to 0 to12 hours.

In some preferred embodiments, the oral butorphanol dosage form providesa mean in vivo extent of absorption of butorphanol from about 0 to about2 hours, or about 0 to about 3 hours, or about 0 to about 4 hours, orabout 0 to about 5 hours, or about 0 to about 6 hours, which is ≦about1% of the mean in vivo extent of absorption from to 0 to 24 hours,wherein the mean in vivo extent of absorption is the area under theplasma or serum butorphanol concentration time curve from the time ofdrug administration to the specified time point. In other embodiments,said in vivo extent of absorption from about 0 to about 2 hours, orabout 0 to about 3 hours, or about 0 to about 4 hours, or about 0 toabout 5 hours, or about 0 to about 6 hours is ≦about 2%, or ≦about 3%,or ≦about 4%, or ≦about 5%, or ≦about 6%, or ≦about 7%, or ≦about 8%, or≦about 9%, or ≦about 10%, or ≦about 12%, or ≦about 14%, or ≦about 15%,or ≦about 16%, or ≦about 18%, or ≦about 20%, or ≦about 25%, or ≦about30%, or ≦about 35% of the mean in vivo extent of absorption from to 0 to24 hours.

In some preferred embodiments, the oral butorphanol dosage form providesa mean in vivo extent of absorption of butorphanol from about 0 to about7 hours, or about 0 to about 8 hours, or about 0 to about 9 hours, orabout 0 to about 10 hours, which is ≦about 1% of the mean in vivo extentof absorption from to 0 to 24 hours, wherein the mean in vivo extent ofabsorption is the area under the plasma or serum butorphanolconcentration time curve from the time of drug administration to thespecified time point. In other embodiments, said in vivo extent ofabsorption from about 0 to about 7 hours, or about 0 to about 8 hours,or about 0 to about 9 hours, or about 0 to about 10 hours is ≦about 2%,or ≦about 3%, or ≦about 4%, or ≦about 5%, or ≦about 6%, or ≦about 7%, or≦about 8%, or ≦about 9%, or ≦about 10%, or ≦about 12%, or ≦about 14%, or≦about 15%, or ≦about 16%, or ≦about 18%, or ≦about 20%, or ≦about 25%or ≦about 30% or ≦about 35%, or ≦about 40%, or ≦about 45%, or ≦about 50%of the mean in vivo extent of absorption from to 0 to 24 hours.

In some preferred embodiments, the oral butorphanol dosage form providesa mean in vivo extent of absorption of butorphanol from about 0 to about2 hours, or about 0 to about 3 hours, or about 0 to about 4 hours, orabout 0 to about 5 hours, or about 0 to about 6 hours, or about 0 toabout 7 hours, or about 0 to about 8 hours, or about 0 to about 9 hours,or about 0 to about 10 hours, which is ≦about 1% of the mean in vivoextent of absorption from to 0 to 36 hours, wherein the mean in vivoextent of absorption is the area under the plasma or serum butorphanolconcentration time curve from the time of drug administration to thespecified time point. In other embodiments, said in vivo extent ofabsorption from about 0 to about 2 hours, or about 0 to about 3 hours,or about 0 to about 4 hours, or about 0 to about 5 hours, or about 0 toabout 6 hours, or about 0 to about 7 hours, or about 0 to about 8 hours,or about 0 to about 9 hours, or about 0 to about 10 hours is ≦about 2%,or ≦about 3%, or ≦about 4%, or ≦about 5%, or ≦about 6%, or ≦about 7%, or≦about 8%, or ≦about 9%, or ≦about 10%, or ≦about 12%, or ≦about 14%, or≦about 15%, or ≦about 16%, or ≦about 18%, or ≦about 20%, or ≦about 25%or ≦about 30% or ≦about 35%, or ≦about 35%, or ≦about 40% or ≦about 45%,or ≦about 50%, or ≦about 60% of the mean in vivo extent of absorptionfrom to 0 to 36 hours.

Resistance to Alcohol Associated Dose Dumping

Another aspect of the invention provides for dosage forms of extendedrelease butorphanol which are resistant to alcohol induced dose dumping.Extended release opioids which do not evidence dose dumping in relationto alcohol intake, which do not evidence clinically significant changesin rate or extent of absorption in relation to alcohol intake, which donot evidence clinically significant pharmacodynamic variability inrelation to alcohol intake, and which do not evidence bio-inequivalenceof the dosage form when given with or without alcohol provide asignificant therapeutic advantage.

In 2005, a serious new clinical problem arose with the therapeutic useof extended release opioids, particularly extended releasemultiparticulate capsule dosage forms, when co-ingested with alcohol.Although subjects with chronic pain are discouraged from using opioidswith alcohol, such co-ingestion in the setting of intractable pain israther widespread. In addition, when used for non-medical purposes(e.g., to obtain a euphoric effect by recreational drug users), opioidsare often used concomitantly with alcohol. This co-ingestion providesadditional mood altering effects desired by the non-medical user.Regardless of whether the concomitant use of opioids and alcohol is formedical or non-medical purposes, any impact of alcohol on the integrityof an extended release dosage form of an opioid can produce additionaltoxicity from alcohol induced dose dumping.

The problem of alcohol induced dose dumping for extended release opioidswas discovered with a once-a-day extended release multiparticulateformulation of hydromorphone HCL (Palladone™ capsules). Palladone™ wasintroduced in the United States and Canada in 2004. In 2005, Palladone™was withdrawn from the market in both countries due to dose-dumping whenco-ingested with alcohol. Patients consuming Palladone™ with 240 mL of40% ethanol had a 6-fold mean increase in peak plasma hydromorphoneconcentration compared with co-ingestion with water. One subjectexperienced a 16-fold increase. Patients consuming 240 mL of 20% ethanolhad a 2-fold mean increase in peak plasma hydromorphone concentration.One subject experienced a 6-fold increase. In some subjects, 8 ounces of4% alcohol (equivalent to ⅔ of a typical serving of beer) resulted inalmost twice the peak plasma hydromorphone concentration. In requestingthe withdrawal of Palladone™, FDA noted that the manufacturer of“drinking alcohol while taking Palladone™ capsules may cause rapidrelease of hydromorphone, leading to high drug levels in the body, withpotentially fatal effects. High drug levels of hydromorphone may depressor stop breathing, cause coma, and even cause death. The Agency hasconcluded that the overall risk versus benefit profile of Palladone™ isunfavorable due to a potentially fatal interaction with alcohol.Pharmacokinetic data indicate that the co-ingestion of Palladone™ andalcohol results in dangerous increases in the peak plasma concentrationsof hydromorphone. These elevated levels may be lethal, even in opioidtolerant patients.” (Sloan and Babul, Expert Opinion on Drug Delivery2006; 3:489-97)

FDA has since noted that a number of other controlled release opioidsmay be similarly vulnerable to dose dumping when co-ingested withalcohol. In vitro studies of alcohol dose dumping studies performed bythe FDA demonstrated that Avinza™ (once-daily extended release morphine)release was alcohol concentration-dependent, leading to a more rapidrelease of morphine. FDA the mandated a “Black Box” warning which states“consumption of alcohol while taking Avinza may result in the rapidrelease and absorption of a potentially fatal dose of morphine” (Sloanand Babul, Expert Opinion on Drug Delivery 2006; 3:489-97; Avinza™ U.S.Prescribing Information, April, 2008). Similarly, when evaluated withalcohol, Opana™ ER (twice-daily extended release oxymorphone)demonstrates significant dose dumping. The mean oxymorphone peak plasmaconcentration increase was 70% and 31%, after concomitant administrationof 240 mL of 40% and 20% ethanol, respectively. In individual subjects,oxymorphone peak plasma concentrations increased by up to about 260%.Similarly, the mean extent of absorption was numerically higher by 13%after co-administration of 240 mL of 40% alcohol (U.S. PrescribingInformation for Opana™ ER).

In some preferred embodiments, the invention provides a method ofprotecting from ethanol induced dose-dumping in a population whichincludes subjects that can be expected to at least occasionallyco-ingest the dosage form with ethanol comprising administering atherapeutically effective amount of oral butorphanol and a controlledrelease material to render said dosage form delayed onset, extendedrelease.

In some preferred embodiments, the invention provides a method ofprotecting from ethanol induced dose-dumping in a population whichincludes subjects that can be expected to at least occasionallyco-ingest the dosage form with ethanol comprising administering atherapeutically effective amount of oral butorphanol and a controlledrelease material to render said dosage form extended release suitablefor twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, wherein, upon co-ingestion with 120mL of a 40% solution of ethanol, said dosage form provides a meanC_(max) difference of less than about 90% when compared with the samedose of said dosage given with 120 mL of water. In other embodiments,the foregoing volume of ethanol and water is 180 mL or 240 mL. In otherembodiments, the foregoing mean C_(max) difference is less than about80%, or less than about 70%, or less than about 60%, or less than about50%, or less than about 45%, or less than about 40%, or less than about35%, or less than about 30%, or less than about 25%, or less than about20%, or less than about 15%.

In some preferred embodiments, the invention provides a method ofprotecting from ethanol induced dose-dumping in a population whichincludes subjects that can be expected to at least occasionallyco-ingest the dosage form with ethanol comprising administering atherapeutically effective amount of oral butorphanol and a controlledrelease material to render said dosage form extended release suitablefor twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, wherein, upon co-ingestion with 120mL of a 40% solution of ethanol, said dosage form provides a mean areaunder the plasma butorphanol concentration time curve from 0 to one hourafter dosing (AUC_(0-1hour)) difference of less than about 90% whencompared with the same dose of said dosage given with 120 mL of water.In other embodiments, the foregoing volume of ethanol and water is 180mL or 240 mL. In other embodiments, the foregoing mean AUC_(0-1hour)difference is less than about 80%, or less than about 70%, or less thanabout 60%, or less than about 50%, or less than about 45%, or less thanabout 40%, or less than about 35%, or less than about 30%, or less thanabout 25%, or less than about 20%, or less than about 15%. In otherembodiments, the foregoing area under the plasma concentration timecurve is from zero to two hours after dosing (AUC_(0-2hour)). In otherembodiments, the foregoing area under the plasma concentration timecurve is from zero to three hours after dosing (AUC_(0-3hour)).

In some preferred embodiments, the dosage form comprises an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and a controlled release material to render said dosageform extended release administration wherein the butorphanol C_(max) issubstantially independent of alcohol intake in that a difference, at anygiven time, between the mean C_(max) of butorphanol administered withabout 30 mL to about 240 mL of a 40% ethanol solution and the meanC_(max) of butorphanol administered without concurrent alcohol (i.e., inan alcohol free state) is less than about 90%. In other preferredembodiments, said difference in mean C_(max) of butorphanol is less thanabout 80%, or less than about 70%, or less than about 60%, or less thanabout 50%, or less than about 45%, or less than about 40%, or less thanabout 35%, or less than about 30%, or less than about 25%, or less thanabout 20%, or less than about 15%.

In some preferred embodiments, the dosage form comprises an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and a controlled release material to render said dosageform extended release administration wherein the difference in mean areaunder the plasma butorphanol concentration time curve from 0 to one hourafter dosing (AUC_(0-1hour)) is substantially independent of alcoholintake in that a difference between the mean butorphanol AUC_(0-1hour)with about 30 mL to about 240 mL of a 40% ethanol solution and with anequal amount of water (i.e., in an alcohol free state) is less thanabout 90%. In other preferred embodiments, said difference in meanAUC_(0-1hour) of butorphanol is less than about 80%, or less than about70%, or less than about 60%, or less than about 50%, or less than about45%, or less than about 40%, or less than about 35%, or less than about30%, or less than about 25%, or less than about 20%, or less than about15%. In other embodiments, the foregoing area under the plasmaconcentration time curve is from zero to two hours after dosing(AUC_(0-2hour)). In other embodiments, the foregoing area under theplasma concentration time curve is from zero to three hours after dosing(AUC_(0-3hour)).

Resistance to Food Associated Dose Dumping

Another aspect of the invention provides for dosage forms of extendedrelease butorphanol which are resistant to fed fasted pharmacokineticvariability. Extended release opioids which do not evidence dose dumpingin relation to food intake, which do not evidence clinically significantchanges in rate or extent of absorption in relation to food intake,which do not evidence clinically significant pharmacodynamic variabilityin relation to food intake, and which do not evidence bio-inequivalenceof the dosage form when given in a fed or fasted state provide asignificant therapeutic advantage.

An important issue with oral extended release products is its potentialfor “dose dumping” in relation to food, where the active drug, intendedfor slow release, is instead released rapidly, resulting in toxicity onthe one hand and a decreased duration of effect on the other. Concurrentintake of food may increase, decrease or have no effect on thebioavailability of pharmaceutical products. The ability to resist foodrelated changes in bioavailability is both a therapeutic benefit and acompetitive marketing advantage.

Many commercialized extended release opioids have been shown to have asignificant food effect. For example, the U.S. prescribing informationfor OxyContin™ (oxycodone ER) states “Food has no significant effect onthe extent of absorption of oxycodone from OxyContin. However, the peakplasma concentration of oxycodone increased by 25% when an OxyContin 160mg Tablet was administered with a high-fat meal”.

The U.S. prescribing information for Avinza™ (morphine ER) states “Whena 60 mg dose of AVINZA was administered immediately following a high fatmeal, peak morphine concentrations and AUC values were similar to thoseobserved when the dose of AVINZA was administered in a fasting state,although achievement of initial concentrations was delayed byapproximately 1 hour under fed conditions.”

According to the FDA “food caused a 16.9% increase in Cmax shiftingt_(max) from 21.06 hour to 8.54 hour” with Palladone™ (hydromorphoneER), (Palladone™ New Drug Application No. 21-044, FDA Summary Basis forApproval).

The U.S. prescribing information for Kadian™ (morphine ER) states “Whileconcurrent administration of food slows the rate of absorption ofKADIAN™, the extent of absorption is not affected and KADIAN™ can beadministered without regard to meals”.

The U.S. prescribing information for Opana™ ER (oxymorphone ER) states“two studies examined the effect of food on the bioavailability ofsingle doses of 20 and 40 mg of OPANA ER in healthy volunteers. In bothstudies, after the administration of OPANA ER, the C_(max) was increasedby approximately 50% in fed subjects compared to fasted subjects. Asimilar increase in C_(max) was also observed with oxymorphonesolution.”

Fed-fasted effects on oral bioavailability of extended release opioidsare not limited to dose dumping in the presence of food or a high fatmeal. For example, an extended release abuse deterrent dosage form ofoxycodone (Remoxy™) which is currently under FDA review for marketingauthorization purportedly has adequate bioavailability when taken withfood but also purportedly has reduced bioavailability in the fastedstate. The manufacturer of Remoxy™ states that “a food effect studyindicated that administration with food has a significant effect on therate and extent of absorption of oxycodone. The rate of absorption isslower and the extent of absorption is higher; REMOXY should thereforebe taken with food” (NDA 22-324, REMOXY XRT™, FDA Advisory CommitteeBriefing Materials for the Anesthetic Life Support Drugs AdvisoryCommittee Meeting of Nov. 13, 2008). A poster presentation on Remoxy™ atscientific meeting suggests more than a doubling of its extent ofabsorption (AUC₀₋₄₈) in relation to food status (Friedmann et al,Remoxy™, A Novel Drug Candidate, Deters Oxycodone Abuse in Humans, WorldInstitute of Pain Meeting, Barcelona, 2004).

In some preferred embodiments, the invention provides a method ofprotecting from food induced dose-dumping and food associatedvariability in bioavailability comprising administering atherapeutically effective amount of oral butorphanol and a controlledrelease material to render said dosage form delayed onset, extendedrelease.

In some preferred embodiments, the invention provides a method ofreducing the variability in bioavailability when taken with food,compared with the fasted state, comprising administering atherapeutically effective amount of oral butorphanol and a controlledrelease material to render said dosage form extended release suitablefor twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, wherein the mean butorphanol C_(max)is substantially independent of food intake in that a difference, at anygiven time, between the C_(max) of butorphanol administered in fastedstate and the mean C_(max) of butorphanol administered in fed state(using a standardized meal) is less than about 90%. In other preferredembodiments, said difference in the mean C_(max) of butorphanol is lessthan about 80%, or less than about 70%, or less than about 60%, or lessthan about 50%, or less than about 45%, or less than about 40%, or lessthan about 35%, or less than about 30%, or less than about 25%, or lessthan about 20%, or less than about 15%.

In some preferred embodiments, the invention provides a method ofreducing the variability in bioavailability when taken with food,compared with the fasted state, comprising administering atherapeutically effective amount of oral butorphanol and a controlledrelease material to render said dosage form extended release suitablefor twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, mean area under the plasmabutorphanol concentration time curve from 0 to one hour after dosing(AUC_(0-1hour)) is substantially independent of food intake in that adifference, at any given time, between the AUC_(0-1hour) of butorphanoladministered in fasted state and the mean AUC_(0-1hour) of butorphanoladministered in fed state (using a standardized meal) is less than about90%. In other preferred embodiments, said difference in the meanAUC_(0-1hour) of butorphanol is less than about 80%, or less than about70%, or less than about 60%, or less than about 50%, or less than about45%, or less than about 40%, or less than about 35%, or less than about30%, or less than about 25%, or less than about 20%, or less than about15%. In other embodiments, the foregoing area under the plasmaconcentration time curve is from zero to two hours after dosing(AUC_(0-2hour)). In other embodiments, the foregoing area under theplasma concentration time curve is from zero to three hours after dosing(AUC_(0-3hour)).

In some preferred embodiments, the invention provides a method ofreducing the variability in bioavailability when taken with food,compared with the fasted state, comprising administering atherapeutically effective amount of oral butorphanol and a controlledrelease material to render said dosage form extended release suitablefor twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN)administration to a human patient, mean area under the plasmabutorphanol concentration time (AUC₀₋₁₂) is substantially independent offood intake in that a difference, at any given time, between the AUC₀₋₁₂of butorphanol administered in fasted state and the mean AUC₀₋₁₂ ofbutorphanol administered in fed state (using a standardized meal) isless than about 90%. In other preferred embodiments, said difference inthe mean AUC₀₋₁₂ of butorphanol is less than about 80%, or less thanabout 70%, or less than about 60%, or less than about 50%, or less thanabout 45%, or less than about 40%, or less than about 35%, or less thanabout 30%, or less than about 25%, or less than about 20%, or less thanabout 15%. In other embodiments, the foregoing area under the plasmaconcentration time curve is AUC_(0-24hours). In other embodiments, theforegoing area under the plasma concentration time curve is AUC_(0-inf).

In some preferred embodiments, the dosage form comprises an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and a controlled release material to render said dosageform extended release administration wherein the mean butorphanolC_(max) is substantially independent of food intake in that adifference, at any given time, between the C_(max) of butorphanoladministered in fasted state and the mean C_(max) of butorphanoladministered in fed state (using a standardized meal) is less than about90%. In other preferred embodiments, said difference in the mean C_(max)of butorphanol is less than about 80%, or less than about 70%, or lessthan about 60%, or less than about 50%, or less than about 45%, or lessthan about 40%, or less than about 35%, or less than about 30%, or lessthan about 25%, or less than about 20%, or less than about 15%.

In some preferred embodiments, the dosage form comprises an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and a controlled release material to render said dosageform extended release administration wherein the mean area under theplasma butorphanol concentration time curve from 0 to one hour afterdosing (AUC_(0-1hour)) is substantially independent wherein the meanbutorphanol AUC_(0-1hour) is substantially independent of food intake inthat a difference, at any given time, between the AUC_(0-1hour) ofbutorphanol administered in fasted state and the mean AUC_(0-1hour) ofbutorphanol administered in fed state (using a standardized meal) isless than about 90%. In other preferred embodiments, said difference inthe mean AUC_(0-1hour) of butorphanol is less than about 80%, or lessthan about 70%, or less than about 60%, or less than about 50%, or lessthan about 45%, or less than about 40%, or less than about 35%, or lessthan about 30%, or less than about 25%, or less than about 20%, or lessthan about 15%. In other embodiments, the foregoing area under theplasma concentration time curve is from zero to two hours after dosing(AUC_(0-2hour)). In other embodiments, the foregoing area under theplasma concentration time curve is from zero to three hours after dosing(AUC_(0-3hour)).

In some preferred embodiments, the dosage form comprises an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol and a controlled release material to render said dosageform extended release administration wherein the mean area under theplasma butorphanol concentration time curve (AUC₀₋₁₂) is substantiallyindependent of food intake in that a difference, at any given time,between the AUC₀₋₁₂ of butorphanol administered in fasted state and themean AUC₀₋₁₂ of butorphanol administered in fed state (using astandardized meal) is less than about 90%. In other preferredembodiments, said difference in the mean AUC₀₋₁₂ of butorphanol is lessthan about 80%, or less than about 70%, or less than about 60%, or lessthan about 50%, or less than about 45%, or less than about 40%, or lessthan about 35%, or less than about 30%, or less than about 25%, or lessthan about 20%, or less than about 15%. In other embodiments, theforegoing area under the plasma concentration time curve isAUC_(0-24hours). In other embodiments, the foregoing area under theplasma concentration time curve is AUC_(0-inf).

Dissolution

In some preferred embodiments, the dosage form is coated with a film orincorporates material which makes the dosage form: (i) is non-dissolvingat pH<3 to 4 and dissolving at pH>5; or (ii) non-dissolving at pH<3 to 4and dissolving at pH>5.5; or (iii) non-dissolving at pH<3 to 4 anddissolving at pH>6; or (iv) non-dissolving at pH<3 to 4.5 and dissolvingat pH>6; or (v) non-dissolving at pH<3 to 4 and dissolving at pH>6.5; or(vi) non-dissolving at pH<3 to 4.5, and dissolving at pH>6.5; or (vii)non-dissolving at pH<3 to 4 and dissolving at pH>7; or (viii)non-dissolving at pH<3 to 4.5 and dissolving at pH>7; or (ix) isnon-dissolving at pH<3 to 5 and dissolving at pH>7; or (x)non-dissolving at pH<3 to 5.5 and dissolving at pH>7.

In some preferred embodiments, the oral butorphanol dosage form isnon-dissolving or substantially non-dissolving at pH<5.5, or at pH<6.0,or at pH<6.2, or at pH<6.5, or at pH<6.8, or at pH<7.0, when measured byUSP Basket Method or USP Paddle Method at 100 rpm in 900 mL of water at37° C. (adjusted to the required pH with hydrochloric acid or sodiumhydroxide) for up to about 2, 2.5, 3, 3.5, 4, 4.5, or 5.

In some preferred embodiments, the oral butorphanol dosage form isnon-releasing or substantially non-releasing at pH<5.5, or at pH<6.0, orat pH<6.2, or at pH<6.5, or at pH<6.8, or at pH<7.0, when measured byUSP Basket Method or USP Paddle Method at 100 rpm in 900 mL of water at37° C. (adjusted to the required pH with hydrochloric acid or sodiumhydroxide) for up to about 2, 2.5, 3, 3.5, 4, 4.5, or 5.

In some preferred embodiments, the oral modified release butorphanoldosage form releases less than about 0.1%, or 0.5%, or 1%, or 1.5%, or2%, or 2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or 5%, or 6%, or 7%, or 8%,or 9%, or 10%, or 12%, or 14%, or 15%, or 16%, or 17%, or 18%, or 20% ofbutorphanol in vitro from the dosage form when measured at about 1, 1.5,2, 2.5, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 hours, said invitro release measured by the USP Basket or Paddle Method at 100 rpm in100 to 900 mL in one or more of the following: (a) water at 37° C. at apH of 4.5, adjusted with HCl; (b) water at 37° C. at a pH of 5, adjustedwith HCl; (c) water at 37° C. at a pH of 5.5, adjusted with HCl; (d)simulated gastric fluid at 37° C.; (e) simulated intestinal fluid at 37°C.; (f) simulated gastric fluid at 37° C. for one hour followed by aswitch to simulated intestinal fluid; (g) Phosphate buffer 0.067M (pH7.0) at 37° C.; and (h) Phosphate buffer 0.067M (pH 7.0) containingTween 80 at 37° C. In some embodiments, said in vitro dissolution ismeasured by the USP Apparatus III (Reciprocating Cylinder) Methodinstead of the Basket or Paddle Method. In some embodiments, mostpreferably, the dosage form releases less than about 0.1%, or 0.5%, or1%, or 1.5%, or 2%, or 2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or 5%, or6%, or 7%, or 8%, or 9%, or 10 of butorphanol in vitro from the dosageform when measured at about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5,or 7 hours.

In some preferred embodiments, the oral modified release butorphanoldosage form is coated with a material or incorporates material which isnon-dissolving or substantially resistant to dissolution, each whenmeasured by USP Basket Method or USP Paddle Method at 100 rpm in 900 mLof water at 37° C. (adjusted to the required pH with hydrochloric acidor sodium hydroxide) at about pH 2, pH 2.2, pH 2.4, pH 2.6, pH 2.8, pH3, pH 3.2, pH 3.4, pH 3.6, pH 3.8, pH 4, pH 4.2, pH 4.4, pH 4.6, pH 4.8,pH 5, pH 5.2, pH 5.4, pH 5.6, pH 5.8, pH 6, pH 6.2, pH 6.4, pH 6.6, pH6.8, pH 7, most preferably at a pH between 5 and 6.2, for at least up toabout 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 hours.

In some preferred embodiments, the oral modified release butorphanoldosage form is coated with a material or incorporates material which isnon-releasing or substantially non-releasing, each when measured by USPBasket Method or USP Paddle Method at 100 rpm in 900 mL of water at 37°C. (adjusted to the required pH with hydrochloric acid or sodiumhydroxide) at about pH 2, pH 2.2, pH 2.4, pH 2.6, pH 2.8, pH 3, pH 3.2,pH 3.4, pH 3.6, pH 3.8, pH 4, pH 4.2, pH 4.4, pH 4.6, pH 4.8, pH 5, pH5.2, pH 5.4, pH 5.6, pH 5.8, pH 6, pH 6.2, pH 6.4, pH 6.6, pH 6.8, pH 7,pH 7.2, pH 7.4, most preferably at a pH between 5 and 6.2, for at leastup to about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 hours.

In some preferred embodiments, the oral modified release butorphanoldosage form is coated with a material or incorporates material which isnon-dissolving or substantially non-dissolving at one pH but dissolvingor substantially dissolving at another pH for up to at least about 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 hours; said one pH being ≦2, or≦2.1, or ≦2.2, or ≦2.3, or ≦2.4, or ≦2.5, or ≦2.6, or ≦2.7, or ≦2.8, or≦2.9, or ≦3, or ≦3.1, or ≦3.2, or ≦3.3, or ≦3.4, or ≦3.5, or ≦3.6, or≦3.7, or ≦3.8, or ≦3.9, or ≦4, or ≦4.1, or ≦4.2, or ≦4.3, or ≦4.4, or≦4.5, or ≦4.6, or ≦4.7, or ≦4.8, or ≦4.9, or ≦5; said another pH being≧5.2, or ≧5.3, or ≧5.4, or ≧5.5, or ≧5.6, or ≧5.7, or ≧5.8, or ≧5.9, or≧6, or ≧6.1, or ≧6.2, or ≧6.3, or ≧6.4, or ≧6.5, or ≧6.6, or ≧6.7, or≧6.8, or ≧6.9, or ≧7, or ≧7.1, or ≧7.2, or ≧7.3, or ≧7.4, or ≧7.5, or≧7.6, or ≧7.7, or ≧7.8, or ≧7.9, or ≧8.0, or ≧8.1, or ≧8.2, or ≧8.3, or≧8.4, or ≧8.5, or ≧8.6, or ≧8.7, or ≧8.8, or ≧8.9, or ≧9.0, each whenmeasured when by USP Basket Method or USP Paddle Method at 100 rpm in900 mL of water at 37° C. (adjusted to the required pH with hydrochloricacid or sodium hydroxide). Preferably, said one pH is ≦4 and saidanother pH is ≧6.5; most preferably, said one pH is ≦5 and said anotherpH is ≧6.

In some preferred embodiments, the oral modified release butorphanoldosage form is coated with a material or incorporates material which isnon-releasing or substantially non-releasing at one pH but releasing orsubstantially releasing at another pH for at least up to about 0.5, 1,1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 hours; said one pH being ≦2, or ≦2.1,or ≦2.2, or ≦2.3, or ≦2.4, or ≦2.5, or ≦2.6, or ≦2.7, or ≦2.8, or ≦2.9,or ≦3, or ≦3.1, or ≦3.2, or ≦3.3, or ≦3.4, or ≦3.5, or ≦3.6, or ≦3.7, or≦3.8, or ≦3.9, or ≦4, or ≦4.1, or ≦4.2, or ≦4.3, or ≦4.4, or ≦4.5, or≦4.6, or ≦4.7, or ≦4.8, or ≦4.9, or ≦5; said another pH being ≧5.2, or≧5.3, or ≧5.4, or ≧5.5, or ≧5.6, or ≧5.7, or ≧5.8, or ≧5.9, or ≧6, or≧6.1, or ≧6.2, or ≧6.3, or ≧6.4, or ≧6.5, or ≧6.6, or ≧6.7, or ≧6.8, or≧6.9, or ≧7, or ≧7.1, or ≧7.2, or ≧7.3, or ≧7.4, or ≧7.5, or ≧7.6, or≧7.7, or ≧7.8, or ≧7.9, or ≧8.0, or ≧8.1, or ≧8.2, or ≧8.3, or ≧8.4, or≧8.5, or ≧8.6, or ≧8.7, or ≧8.8, or ≧8.9, or ≧9.0, each when measuredwhen by USP Basket Method or USP Paddle Method at 100 rpm in 900 mL ofwater at 37° C. (adjusted to the required pH with hydrochloric acid orsodium hydroxide). Preferably, said one pH is ≦4 and said another pH is≧6.5; most preferably, said one pH is ≦5 and said another pH is ≧6.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol, and a controlled release material to render said dosageform suitable for three times-a-day (Q8H or Q8H PRN) administration to ahuman patient; said dosage form providing an in-vitro release rate byweight of butorphanol, when measured by the USP Basket or Paddle Methodat 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at37° C. of from 0% to about 47.5% at 1 hour, from about 10% to about 65%at 2 hours, from about 10% to about 90% at 4 hours, from about 15% toabout 95% at 6 hours, and greater than about 65% at 8 hours. In otherpreferred embodiments, the dosage form provides said an in-vitro releaserate of from 0% to about 40% at 1 hour, from about 5% to about 60% at 2hours, from about 10% to about 70% at 4 hours, from about 15% to about90% at 6 hours, and greater than about 50% at 8 hours.

In some embodiments, some of the dissolution rate specifications ofbutorphanol referred to herein are obtained following pretreatment ofthe dosage form using the USP Basket or Paddle Method at 100 rpm in 900mL distilled water at a pH of ≦4.5, ≦5, or ≦5.5 for two hours at 37° C.before a switch to an aqueous buffer at 37° C. at a pH≧6, or ≧6.8 or apH≧7 (instead of the aqueous buffer at a pH of between 1.6 and 7.2),whereupon the clock is reset to time equal to 0.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition comprising a therapeutically effective amountof butorphanol, and a controlled release material to render said dosageform suitable for three times-a-day (Q8H or Q8H PRN) administration to ahuman patient; said dosage form providing an in-vitro release rate byweight of butorphanol, when measured by the USP Basket or Paddle Methodat 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at37° C. of from 0% to about 47.5% at 1 hour, from about 10% to about 65%at 2 hours, from about 15% to about 70% at 4 hours, from about 25% toabout 80% at 6 hours, and greater than about 65% at 8 hours; saidin-vitro release rate being substantially independent of pH in that adifference, at any given time, between an amount of butorphanol releasedat one pH and an amount released at any other pH, when measured in-vitrousing the USP Basket or Paddle Method of USP Drug Release test of U.S.Pharmacopeia (2003) at 100 rpm in 900 ml aqueous buffer, is no greaterthan 30%. In other preferred embodiments, said pH independent in-vitrorelease rate is from 0% to about 47.5% at 1 hour, from about 10% toabout 65% at 2 hours, from about 10% to about 90% at 4 hours, from about15% to about 95% at 6 hours, and greater than about 65% at 8 hours orfrom 0% to about 40% at 1 hour, from about 5% to about 60% at 2 hours,from about 10% to about 70% at 4 hours, from about 15% to about 90% at 6hours, and greater than about 50% at 8 hours.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition for the treatment of a butorphanol responsivemedical condition comprising a therapeutically effective amount ofbutorphanol or pharmaceutically acceptable salts thereof or mixturethereof; and a controlled release material; said dosage form providingan in-vitro butorphanol release rate, when measured by the USP Basket orPaddle Method at 100 rpm in 900 mL of distilled water at 37° C. which issubstantially pH dependent in that a difference, at 1, or 1.5, or 2, or2.5, or 3 hours, between the amount of butorphanol released at a pH of≦0.5, or ≦1, or ≦1.5, or ≦2, or ≦2.5, or ≦3, or ≦3.5, or ≦4, or ≦4.5, or≦5, or ≦5.5 and an amount released at a pH of or ≧5.8, or ≧6, or ≧6.2,or ≧6.4, or ≧6.6, or ≧6.8, or ≧7, or ≧7.1, or ≧7.2, or ≧7.3, or ≧7.4, or≧7.5, or ≧7.6, or ≧7.7, or ≧7.8, or ≧7.9, or ≧8, is greater than about20%, 25%, 35%, 50%, 60%, 75%, 80%, 90%, 100%, 125%, 150%, 175%, 200%,225%, 250%, 275%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%,1000%, or 1200%, 1500%, 2000%, 3000%, 4000%%, 5000%, or 6000%.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition for the treatment of a butorphanol responsivemedical condition comprising a therapeutically effective amount ofbutorphanol or pharmaceutically acceptable salts thereof or mixturethereof; and a controlled release material; said dosage form providingduodenal delivery, jejunal delivery, ileal delivery, ileo-colonicdelivery or colonic delivery; said dosage form providing an in-vitrobutorphanol release rate, when measured by the USP Basket or PaddleMethod at 100 rpm in 900 mL of distilled water at 37° C. which issubstantially pH dependent in that a difference, at 1, or 1.5, or 2, or2.5, or 3 hours, between the amount of butorphanol released at a pH of≦0.5, or ≦1, or ≦1.5, or ≦2, or ≦2.5, or ≦3, or ≦3.5, or ≦4, or ≦4.5, or≦5, or ≦5.5 and an amount released at a pH of ≧5.8, or ≧6, or ≧6.2, or≧6.4, or ≧6.6, or ≧6.8, or ≧7, or ≧7.1, or ≧7.2, or ≧7.3, or ≧7.4, or≧7.5, or ≧7.6, or ≧7.7, or ≧7.8, or ≧7.9, or ≧8, is greater than about20%, 25%, 35%, 50%, 60%, 75%, 80%, 90%, 100%, 125%, 150%, 175%, 200%,225%, 250%, 275%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%,1000%, or 1200%, 1500%, 2000%, 3000%, 4000%%, 5000%, or 6000%.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition for the treatment of a butorphanol responsivemedical condition comprising a therapeutically effective amount ofbutorphanol or pharmaceutically acceptable salts thereof or mixturethereof, and a controlled release material; said dosage form, followingdissolution (pretreatment) with USP Basket or Paddle Method at 100 rpmin 900 mL of 0.1N HCl for two hours at 37° C., providing an in-vitrorelease rate of butorphanol by weight, when measured at about 5, 10, 15,20, 25, 30, 40, 50, or 60 minutes, 1, 1.5, 2, 2.5, 3, 4, 5 6, 7, 8, 10,12, 14, 16, 18, 20, 24 or 30 hours by the USP Basket or Paddle Method at100 rpm in 900 mL distilled water (time=0 hour begins here) at 37° C. ata pH between 4.5 and 8: (i) of less than about 1%, 2%, 3%, 4%, 5%, 10%,15%, 20%, 25%, 30%, 40%, 50%, 60%, 70% 80%, 90% or 100%; or (ii) of lessthan about 1% to about 20% or less than about 2% to about 20% or lessthan about 5% to about 20% or less than about 8% to about 20% or lessthan about 10% to about 20% or less than about 12% to about 20% or lessthan about 15% to about 20% or less than about 1% to about 50% or lessthan about 2% to about 50% or less than about 5% to about 50% or lessthan about 10% to about 50% or less than about 15% to about 50% or lessthan about 20% to about 50% or less than about 30% to about 50% or lessthan about 40% to about 50% or less than about 1% to about 60% or lessthan about 2% to about 60% or less than about 5% to about 60% or lessthan about 10% to about 60% or less than about 15% to about 60% or lessthan about 20% to about 60% or less than about 30% to about 60% or lessthan about 40% to about 60% or less than about 1% to about 70% or lessthan about 2% to about 70% or less than about 5% to about 70% or lessthan about 10% to about 70% or less than about 15% to about 70% or lessthan about 20% to about 70% or less than about 30% to about 70% or lessthan about 50% to about 70% or less than about 1% to about 80% or lessthan about 2% to about 80% or less than about 5% to about 80% or lessthan about 10% to about 80% or less than about 15% to about 80% or lessthan about 20% to about 80% or less than about 30% to about 80% or lessthan about 40% to about 80% or less than about 1% to about 90% or lessthan about 2% to about 90% or less than about 5% to about 90% or lessthan about 10% to about 90% or less than about 15% to about 90% or lessthan about 20% to about 90% or less than about 30% to about 90% or lessthan about 40% to about 90% or about 60% to about 90% or less than about70% to about 90% or less than about 80% to about 90%, or more than about1%, or more than about 5%, or more than about 10%, or more than about15%, or more than about 20%, or more than about 30%, or more than about40%, or more than about 50%, or more than about 55%, or more than about60%, or more than about 70%, or more than about 80%, or more than about85%, or more than about 90%, or more than about 95%, or more than 99%;or (iii) of ≧0.1%, or ≧0.5%, or ≧1%, or ≧5%, ≧10%, or ≧20%, or ≧30%, or≧40%, or ≧50%, or ≧60%, or ≧70%, or ≧80%, or ≧90%, or about 100%.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition for the treatment of a butorphanol responsivemedical condition comprising a therapeutically effective amount ofbutorphanol or pharmaceutically acceptable salts thereof or mixturethereof, and a controlled release material; said dosage form providingduodenal release, jejunal release, ileal release, ileo-colonic releaseor colonic release; said dosage form, following dissolution(pretreatment) with USP Basket or Paddle Method at 100 rpm in 900 mL of0.1N HCl for two hours at 37° C., providing an in-vitro release rate ofbutorphanol by weight, when measured at about 5, 10, 15, 20, 25, 30, 40,50, or 60 minutes, 1, 1.5, 2, 2.5, 3, 4, 5 6, 7, 8, 10, 12, 14, 16, 18,20, 24 or 30 hours by the USP Basket or Paddle Method at 100 rpm in 900mL distilled water (time=0 hour begins here) at 37° C. at a pH between4.5 and 8: (i) of less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%,25%, 30%, 40%, 50%, 60%, 70% 80%, 90% or 100%; or (ii) of less thanabout 1% to about 20% or less than about 2% to about 20% or less thanabout 5% to about 20% or less than about 8% to about 20% or less thanabout 10% to about 20% or less than about 12% to about 20% or less thanabout 15% to about 20% or less than about 1% to about 50% or less thanabout 2% to about 50% or less than about 5% to about 50% or less thanabout 10% to about 50% or less than about 15% to about 50% or less thanabout 20% to about 50% or less than about 30% to about 50% or less thanabout 40% to about 50% or less than about 1% to about 60% or less thanabout 2% to about 60% or less than about 5% to about 60% or less thanabout 10% to about 60% or less than about 15% to about 60% or less thanabout 20% to about 60% or less than about 30% to about 60% or less thanabout 40% to about 60% or less than about 1% to about 70% or less thanabout 2% to about 70% or less than about 5% to about 70% or less thanabout 10% to about 70% or less than about 15% to about 70% or less thanabout 20% to about 70% or less than about 30% to about 70% or less thanabout 50% to about 70% or less than about 1% to about 80% or less thanabout 2% to about 80% or less than about 5% to about 80% or less thanabout 10% to about 80% or less than about 15% to about 80% or less thanabout 20% to about 80% or less than about 30% to about 80% or less thanabout 40% to about 80% or less than about 1% to about 90% or less thanabout 2% to about 90% or less than about 5% to about 90% or less thanabout 10% to about 90% or less than about 15% to about 90% or less thanabout 20% to about 90% or less than about 30% to about 90% or less thanabout 40% to about 90% or about 60% to about 90% or less than about 70%to about 90% or less than about 80% to about 90%, or more than about 1%,or more than about 5%, or more than about 10%, or more than about 15%,or more than about 20%, or more than about 30%, or more than about 40%,or more than about 50%, or more than about 55%, or more than about 60%,or more than about 70%, or more than about 80%, or more than about 85%,or more than about 90%, or more than about 95%, or more than 99%; or(iii) of ≧0.1%, or ≧0.5%, or ≧1%, or ≧5%, ≧10%, or ≧20%, or ≧30%, or≧40%, or ≧50%, or ≧60%, or ≧70%, or ≧80%, or ≧90%, or about 100%.

In some embodiments of the invention, pH adjustments of the dissolutionmedia may be achieved by adjustment as required with hydrochloric acidor sodium hydroxide. In some embodiments of the invention, pHadjustments of the dissolution media may be achieved with otherpharmaceutical excipients, including acids, bases and buffers known inthe art.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition for the treatment of a butorphanol responsivemedical condition comprising a therapeutically effective amount ofbutorphanol or pharmaceutically acceptable salts thereof or mixturethereof, and a controlled release material; said dosage form, followingdissolution (pretreatment) with USP Basket or Paddle Method at 100 rpmin 900 mL of 0.1N HCl for two hours at 37° C., and then followingfurther dissolution (pretreatment) with USP Basket or Paddle Method at100 rpm in 900 mL distilled water at any pH of between 2 and 4 for afurther time of up to two hours at 37° C., providing an in-vitro releaserate by weight of butorphanol, when measured by the USP Basket or PaddleMethod at 100 rpm in 900 mL distilled water (time=0 hour begins here) at37° C. at any pH between 4.5 and 8 at 37° C. (measured at about 5, about10, about 15, about 20, about 25, about 30, about 35, about 40, about45, about 50, about 55 or about 60 minutes, or about 2 hours, or about 3hours, or about 4 hours, or about 5 hours, or about 6 hours, or about 7hours, or about 8 hours, or about 10 hours, or about 12 hours, or about14 hours, or about 16 hours, or about 18 hours, or about 20 hours, orabout 24 hours, or about 30 hours): (i) of less than about 1% to about20% or less than about 2% to about 20% or less than about 5% to about20% or less than about 8% to about 20% or less than about 10% to about20% or less than about 12% to about 20% or less than about 15% to about20% or less than about 1% to about 50% or less than about 2% to about50% or less than about 5% to about 50% or less than about 10% to about50% or less than about 15% to about 50% or less than about 20% to about50% or less than about 30% to about 50% or less than about 40% to about50% or less than about 1% to about 60% or less than about 2% to about60% or less than about 5% to about 60% or less than about 10% to about60% or less than about 15% to about 60% or less than about 20% to about60% or less than about 30% to about 60% or less than about 40% to about60% or less than about 1% to about 70% or less than about 2% to about70% or less than about 5% to about 70% or less than about 10% to about70% or less than about 15% to about 70% or less than about 20% to about70% or less than about 30% to about 70% or less than about 50% to about70% or less than about 1% to about 80% or less than about 2% to about80% or less than about 5% to about 80% or less than about 10% to about80% or less than about 15% to about 80% or less than about 20% to about80% or less than about 30% to about 80% or less than about 40% to about80% or less than about 1% to about 90% or less than about 2% to about90% or less than about 5% to about 90% or less than about 10% to about90% or less than about 15% to about 90% or less than about 20% to about90% or less than about 30% to about 90% or less than about 40% to about90% or about 60% to about 90% or less than about 70% to about 90% orless than about 80% to about 90%, or more than about 1%, or more thanabout 5%, or more than about 10%, or more than about 15%, or more thanabout 20%, or more than about 30%, or more than about 40%, or more thanabout 50%, or more than about 55%, or more than about 60%, or more thanabout 70%, or more than about 80%, or more than about 85%, or more thanabout 90%, or more than about 95%, or more than 99%, or about 100%; or(ii) of ≧0.1%, or ≧0.5%, or ≧1%, or ≧5%, ≧10%, or ≧20%, or ≧30%, or≧40%, or ≧50%, or ≧60%, or ≧70%, or ≧80%, or ≧90%, or about 100. In someembodiments, the foregoing dosage form provides duodenal delivery,jejunal delivery, ileal delivery, ileo-colonic delivery or colonicdelivery.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition for the treatment of a butorphanol responsivemedical condition comprising a therapeutically effective amount ofbutorphanol or pharmaceutically acceptable salts thereof or mixturethereof, and a controlled release material; said dosage form, followingdissolution (pretreatment) with USP Basket or Paddle Method at 100 rpmin 900 mL of 0.1N HCl for two hours at 37° C., and then followingfurther dissolution (pretreatment) with USP Basket or Paddle Method at100 rpm in 900 mL distilled water at any pH of between 2 and 4 for afurther time of up to two hours at 37° C., providing an in-vitro releaserate by weight of butorphanol, when measured by the USP Basket or PaddleMethod at 100 rpm in 900 mL distilled water (time=0 hour begins here) at37° C. at any pH between 4.5 and 8 at 37° C.: (i) from 0% to about 47.5%at 1 hour, from about 10% to about 65% at 2 hours, from about 15% toabout 70% at 4 hours, from about 25% to about 77.5% at 6 hours, fromabout 35% to about 87.5% at 9 hours, and greater than about 65% at 12hours; or (ii) from 0% to about 40% at 1 hour, from about 5% to about55% at 2 hours, from about 10% to about 60% at 4 hours, from about 15%to about 70% at 6 hours, from about 25% to about 80% at 9 hours, andgreater than about 50% at 12 hours. In some embodiments, the foregoingdosage form provides duodenal delivery, jejunal delivery, ilealdelivery, ileo-colonic delivery or colonic delivery.

In some preferred embodiments, the dosage form provides an oralpharmaceutical composition for the treatment of a butorphanol responsivemedical condition comprising a therapeutically effective amount ofbutorphanol or pharmaceutically acceptable salts thereof or mixturethereof; said dosage form, following dissolution (pretreatment) with USPBasket or Paddle Method at 100 rpm in 900 mL of 0.1N HCl for two hoursat 37° C., providing an in-vitro release rate by weight of butorphanol,when measured by the USP Basket or Paddle Method at 100 rpm in 900 mLdistilled water (time=0 hour begins here) at 37° C. at any pH between4.5 and 8 at 37° C.: (1) between 0% to about 47.5% at 1 hour, betweenabout 10% to about 65% at 2 hours, between about 15% to about 70% at 4hours, between about 25% to about 77.5% at 6 hours, between about 35% toabout 87.5% at 9 hours, and greater than about 65% at 12 hours; or (2)between about 10% to about 65% at 4 hours, between about 20% to about70% at 8 hours, between about 25% to about 80% at 12 hours, betweenabout 35% to about 95% at 18 hours, and greater than about 65% at 24hours; or (3) between 0% to about 60% at 1 hour, between about 0% andabout 80% at 2 hours, between about 3% and about 95% at 4 hours andbetween about 10% and about 100% at 8 hours; or (4) between about 10%and about 65% at 1 hour, between about 20% and about 75% at 2 hours,between about 30% and about 95% at 4 hours and between about 40% andabout 100% at 8 hours; or (5) between about 10% to about 65% at 2 hours,between about 15% to about 70% at 4 hours, between about 25% to about77.5% at 6 hours, between about 35% to about 87.5% at 9 hours, andgreater than about 65% at 12 hours; or (6) between about 5% and about50% at 1 hour, between about 10% and about 75% at 2 hours, between about20% and about 95% at 4 hours, between about 40% and about 100% at 8hours, greater than about 50% at 12 hours, greater than about 70% at 18hours, and greater than about 80% at 24 hours; or (7) between about 5%and about 50% at 1 hour, between about 10% and about 75% at 2 hours,between about 20% and about 95% at 4 hours, between about 40% and about100% at 8 hours, greater than about 50% at 12 hours, greater than about70% at 18 hours, and greater than about 80% at 24 hours; or (8) between0% to about 30% at 1 hour, between about 10% to about 65% at 4 hours,between about 20% to about 70% at 8 hours, between about 25% to about80% at 12 hours, between about 35% to about 95% at 18 hours, and greaterthan about 65% at 24 hours; or (9) between 0% to about 50% at 1 hour,between about 0% and about 75% at 2 hours, between about 3% and about95% at 4 hours, between about 10% and about 100% at 8 hours, betweenabout 25% and about 100% at 12 hours, between about 30% and about 100%at 16 hours, between about 50% and about 100% at 24 hours, and greaterthan about 80% at 36 hours; or (10) between about 20% and about 50% at 1hour, between about 40% and about 75% at 2 hours, between about 60% andabout 95% at 4 hours, between about 80% and about 100% at 8 hours andbetween about 90% and about 100% at 12 hours; or (11) between 0% toabout 50% at 1 hour, between about 0% and about 75% at 2 hours, betweenabout 10% and about 95% at 4 hours, between about 35% and about 100% at8 hours, between about 55% and about 100% at 12 hours, between about 70%to about 100% at 16 hours, and greater than about 90% at 24 hours; or(12) between 0% to about 30% at 1 hour, between about 0% and about 45%at 2 hours, between about 3% and about 55% at 4 hours, between about 10%and about 65% at 8 hours, between about 20% and about 75% at 12 hours,between about 30% to about 88% at 16 hours, between about 50% and about100% hours at 24 hours and greater than 80% at 36 hours; or (13) between0% to about 50% at 1 hour, between about 0% and about 75% at 2 hours,between about 3% and about 95% at 4 hours, between about 10% and about100% at 8 hours, between about 20% and about 100% at 12 hours, betweenabout 30% to about 100% at 16 hours, between about 50% and about 100%hours at 24 hours and greater than 80% at 36 hours; or (14) betweenabout 15% and about 25% at 1 hour, between about 25% and about 35% at 2hours, between about 30% and about 45% at 4 hours, between about 40% andabout 60% at 8 hours, between about 55% and about 70% at 12 hours andbetween about 60% to about 75% at 16 hours; or (15) between 0% to about60% at 1 hour, between about 0% and about 80% at 2 hours, between about3% and about 95% at 4 hours and between about 10% and about 100% at 8hours; or (16) between 0% and about 10% at 1 hour, between about 0% andabout 20% at 2 hours, between about 2% and about 80% at 4 hours andbetween about 5% and about 100% at 8 hours; or (17) between 0% and about20% at 1 hour, between about 0% and about 40% at 2 hours, between about0% and about 80% at 4 hours and between about 2% and about 100% at 8hours; or (18) between 0% and about 40% at 1 hour, between about 0% andabout 60% at 2 hours, between about 5% and about 85% at 4 hours andbetween about 5% and about 90% at 8 hours and greater than 20% at 12hours; or (19) between 0% and about 50% at 1 hour, between about 0% andabout 50% at 2 hours, between about 10% and about 90% at 4 hours andbetween about 15% and about 90% at 8 hours and greater than 30% at 12hours; or (20) between 0% and about 70% at 1 hour, between about 0% andabout 70% at 2 hours, between about 10% and about 75% at 4 hours andbetween about 15% and about 90% at 8 hours and greater than 30% at 12hours; or (21) between about 10% and about 65% at 1 hour, between about20% and about 75% at 2 hours, between about 30% and about 95% at 4 hoursand between about 40% and about 100% at 8 hours; or (22) between 2% andabout 70% at 1 hour, between about 5% and about 80% at 2 hours, betweenabout 10% and about 90% at 4 hours and between about 20% and about 100%at 8 hours; or (23) between 5% and about 60% at 1 hour, between about10% and about 75% at 2 hours, between about 15% and about 85% at 4 hoursand between about 30% and about 100% at 8 hours; or (24) between 20% andabout 70% at 1 hour, between about 20% and about 75% at 2 hours, betweenabout 20% and about 90% at 4 hours and between about 40% and about 100%at 8 hours; or (25) between 30% and about 80% at 1 hour, between about40% and about 85% at 2 hours, between about 40% and about 90% at 4 hoursand between about 60% and about 100% at 8 hours; or (26) between 1% andabout 20% at 1 hour, between about 5% and about 20% at 2 hours, betweenabout 10% and about 40% at 4 hours and between about 20% and about 40%at 8 hours and greater than 40% at 12 hours; or (27) between 0% to about47.5% at 1 hour, between about 10% to about 65% at 2 hours, betweenabout 15% to about 70% at 4 hours, between about 25% to about 77.5% at 6hours, between about 35% to about 87.5% at 9 hours, and greater thanabout 65% at 12 hours; or (28) between 0% to about 30% at 1 hour,between about 5% to about 45% at 2 hours, between about 10% to about 60%at 4 hours, between about 15% to about 70% at 6 hours, between about 25%to about 80% at 9 hours, and greater than about 50% at 12 hours; or (29)between 0% to about 20% at 1 hour, between about 2% to about 35% at 2hours, between about 5% to about 50% at 4 hours, between about 10% toabout 60% at 6 hours, between about 15% to about 70% at 9 hours, andgreater than about 40% at 12 hours; or (30) between 0% to about 10% at 1hour, between about 1% to about 30% at 2 hours, between about 5% toabout 40% at 4 hours, between about 10% to about 60% at 6 hours, betweenabout 15% to about 70% at 9 hours, and greater than about 40% at 12hours; or (31) between 0% to about 5% at 1 hour, between about 0% toabout 10% at 2 hours, between about 2% to about 20% at 4 hours, betweenabout 5% to about 30% at 6 hours, between about 10% to about 40% at 9hours, and greater than about 30% at 12 hours; or (32) between 0% toabout 50% at 1 hour, between about 15% to about 70% at 2 hours, betweenabout 20% to about 75% at 4 hours, between about 30% to about 80% at 6hours, between about 30% to about 90% at 9 hours, and greater than about70% at 12 hours; or (33) between 0% to about 60% at 1 hour, betweenabout 15% to about 80% at 2 hours, between about 25% to about 85% at 4hours, between about 35% to about 90% at 6 hours, between about 40% toabout 90% at 9 hours, and greater than about 80% at 12 hours; (34)between 0% to about 70% at 1 hour, between about 20% to about 80% at 2hours, between about 25% to about 80% at 4 hours, between about 35% toabout 80% at 6 hours, between about 40% to about 80% at 9 hours, andgreater than about 60% at 12 hours; or (35) between 0% to about 75% at 1hour, between about 30% to about 80% at 2 hours, between about 35% toabout 90% at 4 hours, between about 50% to about 90% at 6 hours, betweenabout 55% to about 95% at 9 hours, and greater than about 70% at 12hours; or (36) between about 5% and about 50% at 1 hour, between about10% and about 75% at 2 hours, between about 20% and about 95% at 4hours, between about 40% and about 100% at 8 hours, greater than about50% at 12 hours, greater than about 70% at 18 hours, and greater thanabout 80% at 24 hours; or (37) between 2% and about 50% at 1 hour,between about 5% and about 75% at 2 hours, between about 15% and about75% at 4 hours, between about 30% and about 90% at 8 hours, greater thanabout 40% at 12 hours, greater than about 60% at 18 hours, and greaterthan about 70% at 24 hours; or (38) between 1% and about 40% at 1 hour,between about 2% and about 60% at 2 hours, between about 10% and about65% at 4 hours, between about 20% and about 80% at 8 hours, greater thanabout 30% at 12 hours, greater than about 40% at 18 hours, and greaterthan about 60% at 24 hours; or (39) between 5% and about 60% at 1 hour,between about 15% and about 80% at 2 hours, between about 25% and about95% at 4 hours, between about 45% and about 100% at 8 hours, greaterthan about 60% at 12 hours, greater than about 80% at 18 hours, andgreater than about 90% at 24 hours; or (40) between 10% and about 65% at1 hour, between about 20% and about 85% at 2 hours, between about 30%and about 100% at 4 hours, between about 60% and about 100% at 8 hours,greater than about 70% at 12 hours, greater than about 90% at 18 hours,and greater than about 95% at 24 hours; or (41) between 0% to about 30%at 1 hour, between about 10% to about 65% at 4 hours, between about 20%to about 70% at 8 hours, between about 25% to about 80% at 12 hours,between about 35% to about 95% at 18 hours, and greater than about 65%at 24 hours; or (42) between 0% to about 20% at 1 hour, between about 5%to about 50% at 4 hours, between about 10% to about 60% at 8 hours,between about 15% to about 70% at 12 hours, between about 25% to about90% at 18 hours, and greater than about 55% at 24 hours; or (43) between0% to about 10% at 1 hour, between about 5% to about 40% at 4 hours,between about 8% to about 50% at 8 hours, between about 10% to about 60%at 12 hours, between about 22% to about 80% at 18 hours, and greaterthan about 45% at 24 hours; or (44) between 0% to about 35% at 1 hour,between about 15% to about 70% at 4 hours, between about 25% to about75% at 8 hours, between about 30% to about 85% at 12 hours, betweenabout 40% to about 100% at 18 hours, and greater than about 75% at 24hours; or (45) between 0% to about 40% at 1 hour, between about 20% toabout 70% at 4 hours, between about 30% to about 80% at 8 hours, betweenabout 35% to about 90% at 12 hours, between about 45% to about 100% at18 hours, and greater than about 80% at 24 hours; or (46) between 0% toabout 45% at 1 hour, between about 25% to about 75% at 4 hours, betweenabout 35% to about 85% at 8 hours, between about 40% to about 90% at 12hours, between about 50% to about 100% at 18 hours, and greater thanabout 90% at 24 hours; or (47) between 0% to about 50% at 1 hour,between about 30% to about 80% at 4 hours, between about 40% to about90% at 8 hours, between about 45% to about 95% at 12 hours, betweenabout 60% to about 100% at 18 hours, and greater than about 95% at 24hours; or (48) between 0% to about 60% at 1 hour, between about 40% toabout 80% at 4 hours, between about 45% to about 90% at 8 hours, betweenabout 50% to about 100% at 12 hours, between about 70% to about 100% at18 hours, and greater than about 80% at 24 hours; or (49) between 0% andabout 50% at 1 hour, between about 0% and about 75% at 2 hours, betweenabout 3% and about 95% at 4 hours, between about 10% and about 100% at 8hours, between about 25% and about 100% at 12 hours, between about 30%and about 100% at 16 hours, between about 50% and about 100% at 24hours, and greater than about 80% at 36 hours; or (50) between 0% andabout 40% at 1 hour, between about 0% and about 65% at 2 hours, betweenabout 2% and about 85% at 4 hours, between about 8% and about 90% at 8hours, between about 20% and about 95% at 12 hours, between about 25%and about 95% at 16 hours, between about 40% and about 90% at 24 hours,and greater than about 70% at 36 hours; or (51) between 0% and about 30%at 1 hour, between about 0% and about 50% at 2 hours, between about 1%and about 75% at 4 hours, between about 5% and about 80% at 8 hours,between about 10% and about 85% at 12 hours, between about 15% and about90% at 16 hours, between about 30% and about 80% at 24 hours, andgreater than about 70% at 36 hours; or (52) between 0% and about 60% at1 hour, between about 0% and about 80% at 2 hours, between about 5% andabout 100% at 4 hours, between about 15% and about 100% at 8 hours,between about 35% and about 100% at 12 hours, between about 40% andabout 100% at 16 hours, between about 60% and about 100% at 24 hours,and greater than about 85% at 36 hours; or (53) between 0% and about 65%at 1 hour, between about 0% and about 85% at 2 hours, between about 10%and about 100% at 4 hours, between about 20% and about 100% at 8 hours,between about 40% and about 100% at 12 hours, between about 50% andabout 100% at 16 hours, between about 70% and about 100% at 24 hours,and greater than about 90% at 36 hours; or (54) between 0% and about 70%at 1 hour, between about 0% and about 90% at 2 hours, between about 20%and about 100% at 4 hours, between about 30% and about 100% at 8 hours,between about 50% and about 100% at 12 hours, between about 60% andabout 100% at 16 hours, between about 80% and about 100% at 24 hours,and greater than about 95% at 36 hours; or (55) between 20% and about50% at 1 hour, between about 40% and about 75% at 2 hours, between about60% and about 95% at 4 hours, between about 80% and about 100% at 8hours and between about 90% and about 100% at 12 hours; or (56) between15% and about 45% at 1 hour, between about 35% and about 70% at 2 hours,between about 55% and about 90% at 4 hours, between about 75% and about90% at 8 hours and between about 80% and about 95% at 12 hours; or (57)between 10% and about 40% at 1 hour, between about 30% and about 65% at2 hours, between about 50% and about 85% at 4 hours, between about 70%and about 85% at 8 hours and between about 75% and about 90% at 12hours; or (58) between 5% and about 35% at 1 hour, between about 25% andabout 60% at 2 hours, between about 45% and about 80% at 4 hours,between about 65% and about 80% at 8 hours and between about 70% andabout 85% at 12 hours; or (59) between 25% and about 55% at 1 hour,between about 45% and about 80% at 2 hours, between about 65% and about95% at 4 hours, between about 85% and about 100% at 8 hours and betweenabout 95% and about 100% at 12 hours; or (60) between 30% and about 60%at 1 hour, between about 50% and about 80% at 2 hours, between about 70%and about 95% at 4 hours, between about 90% and about 100% at 8 hoursand between about 95% and about 100% at 12 hours; or (61) between 35%and about 60% at 1 hour, between about 50% and about 80% at 2 hours,between about 80% and about 95% at 4 hours, between about 90% and about100% at 8 hours and between about 95% and about 100% at 12 hours; or(62) between 20% and about 40% at 1 hour, between about 40% and about65% at 2 hours, between about 60% and about 85% at 4 hours, betweenabout 70% and about 90% at 8 hours and between about 80% and about 100%at 12 hours; or (63) between 0% and about 50% at 1 hour, between about0% and about 75% at 2 hours, between about 10% and about 95% at 4 hours,between about 35% and about 100% at 8 hours, between about 55% and about100% at 12 hours, between about 70% to about 100% at 16 hours, andgreater than about 90% at 24 hours; or (64) between 0% and about 40% at1 hour, between about 0% and about 65% at 2 hours, between about 8% andabout 85% at 4 hours, between about 30% and about 90% at 8 hours,between about 45% and about 100% at 12 hours, between about 60% to about100% at 16 hours, and greater than about 80% at 24 hours; or (66)between 0% and about 30% at 1 hour, between about 0% and about 55% at 2hours, between about 5% and about 75% at 4 hours, between about 20% andabout 80% at 8 hours, between about 35% and about 100% at 12 hours,between about 50% to about 100% at 16 hours, and greater than about 70%at 24 hours; or (67) between 0% and about 20% at 1 hour, between about0% and about 45% at 2 hours, between about 5% and about 65% at 4 hours,between about 10% and about 70% at 8 hours, between about 25% and about80% at 12 hours, between about 40% to about 100% at 16 hours, andgreater than about 60% at 24 hours; or (68) between 0% and about 60% at1 hour, between about 0% and about 80% at 2 hours, between about 15% andabout 95% at 4 hours, between about 40% and about 100% at 8 hours,between about 60% and about 100% at 12 hours, between about 75% to about100% at 16 hours, and greater than about 90% at 24 hours; or (69)between 0% and about 65% at 1 hour, between about 0% and about 85% at 2hours, between about 20% and about 90% at 4 hours, between about 45% andabout 100% at 8 hours, between about 65% and about 100% at 12 hours,between about 80% to about 100% at 16 hours, and greater than about 90%at 24 hours; or (70) between 0% and about 40% at 1 hour, between about0% and about 50% at 2 hours, between about 10% and about 80% at 4 hours,between about 25% and about 70% at 8 hours, between about 40% and about80% at 12 hours, between about 60% to about 100% at 16 hours, andgreater than about 90% at 24 hours; or (71) between 0% and about 30% at1 hour, between about 0% and about 45% at 2 hours, between about 3% andabout 55% at 4 hours, between about 10% and about 65% at 8 hours,between about 20% and about 75% at 12 hours, between about 30% to about88% at 16 hours, between about 50% and about 100% hours at 24 hours andgreater than 80% at 36 hours; or (72) between 0% and about 25% at 1hour, between about 0% and about 40% at 2 hours, between about 2% andabout 50% at 4 hours, between about 8% and about 60% at 8 hours, betweenabout 10% and about 70% at 12 hours, between about 25% to about 80% at16 hours, between about 45% and about 100% hours at 24 hours and greaterthan 75% at 36 hours; or (73) between 0% and about 20% at 1 hour,between about 0% and about 35% at 2 hours, between about 1% and about45% at 4 hours, between about 5% and about 55% at 8 hours, between about8% and about 65% at 12 hours, between about 20% to about 75% at 16hours, between about 40% and about 100% hours at 24 hours and greaterthan 70% at 36 hours; or (74) between 0% and about 15% at 1 hour,between about 0% and about 30% at 2 hours, between about 0% and about40% at 4 hours, between about 5% and about 50% at 8 hours, between about8% and about 60% at 12 hours, between about 15% to about 70% at 16hours, between about 35% and about 100% hours at 24 hours and greaterthan 60% at 36 hours; or (75) between 0% and about 10% at 1 hour,between about 0% and about 25% at 2 hours, between about 0% and about35% at 4 hours, between about 5% and about 45% at 8 hours, between about10% and about 50% at 12 hours, between about 10% to about 60% at 16hours, between about 30% and about 90% hours at 24 hours and greaterthan 70% at 36 hours; or (76) between 0% and about 35% at 1 hour,between about 0% and about 50% at 2 hours, between about 5% and about60% at 4 hours, between about 15% and about 70% at 8 hours, betweenabout 25% and about 80% at 12 hours, between about 35% to about 90% at16 hours, between about 55% and about 100% hours at 24 hours and greaterthan 85% at 36 hours; or (77) between 0% and about 40% at 1 hour,between about 0% and about 55% at 2 hours, between about 10% and about65% at 4 hours, between about 20% and about 75% at 8 hours, betweenabout 30% and about 85% at 12 hours, between about 40% to about 100% at16 hours, between about 55% and about 100% hours at 24 hours and greaterthan 90% at 36 hours; or (78) between 0% and about 45% at 1 hour,between about 0% and about 60% at 2 hours, between about 15% and about70% at 4 hours, between about 25% and about 80% at 8 hours, betweenabout 35% and about 90% at 12 hours, between about 45% to about 100% at16 hours, between about 60% and about 100% hours at 24 hours and greaterthan 60% at 36 hours; or (79) between 0% and about 50% at 1 hour,between about 5% and about 65% at 2 hours, between about 20% and about75% at 4 hours, between about 30% and about 85% at 8 hours, betweenabout 40% and about 95% at 12 hours, between about 50% to about 100% at16 hours, between about 70% and about 100% hours at 24 hours and greaterthan 70% at 36 hours; or (80) between 0% and about 30% at 1 hour,between about 5% and about 40% at 2 hours, between about 10% and about60% at 4 hours, between about 20% and about 70% at 8 hours, betweenabout 30% and about 100% at 12 hours, between about 40% to about 100% at16 hours, between about 60% and about 100% hours at 24 hours and greaterthan 90% at 36 hours; or (81) between 0% and about 30% at 1 hour,between about 0% and about 30% at 2 hours, between about 0% and about30% at 4 hours, between about 5% and about 70% at 8 hours, between about10% and about 80% at 12 hours, between about 20% to about 100% at 16hours, between about 40% and about 100% hours at 24 hours and greaterthan 50% at 36 hours; or (82) between 0% and about 20% at 1 hour,between about 0% and about 20% at 2 hours, between about 0% and about20% at 4 hours, between about 0% and about 20% at 8 hours, between about5% and about 40% at 12 hours, between about 10% to about 80% at 16hours, between about 40% and about 100% hours at 24 hours and greaterthan 60% at 36 hours; or (83) between 0% and about 10% at 1 hour,between about 0% and about 20% at 2 hours, between about 0% and about40% at 4 hours, between about 5% and about 60% at 8 hours, between about10% and about 80% at 12 hours, between about 20% to about 100% at 16hours, between about 40% and about 100% hours at 24 hours and greaterthan 50% at 36 hours; or (84) between 0% and about 50% at 1 hour,between about 0% and about 75% at 2 hours, between about 3% and about95% at 4 hours, between about 10% and about 100% at 8 hours, betweenabout 20% and about 100% at 12 hours, between about 30% to about 100% at16 hours, between about 50% and about 100% hours at 24 hours and greaterthan 80% at 36 hours; or (85) between 0% and about 45% at 1 hour,between about 0% and about 70% at 2 hours, between about 3% and about90% at 4 hours, between about 8% and about 100% at 8 hours, betweenabout 15% and about 100% at 12 hours, between about 25% to about 100% at16 hours, between about 45% and about 100% hours at 24 hours and greaterthan 80% at 36 hours; or (86) between 0% and about 40% at 1 hour,between about 0% and about 65% at 2 hours, between about 0% and about80% at 4 hours, between about 5% and about 80% at 8 hours, between about10% and about 90% at 12 hours, between about 20% to about 100% at 16hours, between about 40% and about 100% hours at 24 hours and greaterthan 70% at 36 hours; or (87) between 0% and about 35% at 1 hour,between about 0% and about 60% at 2 hours, between about 0% and about70% at 4 hours, between about 3% and about 70% at 8 hours, between about5% and about 80% at 12 hours, between about 15% to about 100% at 16hours, between about 30% and about 100% hours at 24 hours and greaterthan 40% at 36 hours; or (88) between 0% and about 60% at 1 hour,between about 0% and about 80% at 2 hours, between about 5% and about100% at 4 hours, between about 15% and about 100% at 8 hours, betweenabout 30% and about 100% at 12 hours, between about 40% to about 100% at16 hours, between about 60% and about 100% hours at 24 hours and greaterthan 70% at 36 hours; or (89) between 0% and about 50% at 1 hour,between about 0% and about 75% at 2 hours, between about 5% and about95% at 4 hours, between about 25% and about 80% at 8 hours, betweenabout 30% and about 100% at 12 hours, between about 40% to about 100% at16 hours, between about 60% and about 100% hours at 24 hours and greaterthan 60% at 36 hours; or (90) between 0% and about 60% at 1 hour,between about 0% and about 85% at 2 hours, between about 5% and about100% at 4 hours, between about 10% and about 100% at 8 hours, betweenabout 20% and about 100% at 12 hours, between about 30% to about 100% at16 hours, between about 50% and about 100% hours at 24 hours and greaterthan 80% at 36 hours; or (91) between 15% and about 25% at 1 hour,between about 25% and about 35% at 2 hours, between about 30% and about45% at 4 hours, between about 40% and about 60% at 8 hours, betweenabout 55% and about 70% at 12 hours and between about 60% to about 75%at 16 hours; or (92) between 10% and about 20% at 1 hour, between about20% and about 30% at 2 hours, between about 25% and about 40% at 4hours, between about 30% and about 50% at 8 hours, between about 50% andabout 65% at 12 hours and between about 55% to about 65% at 16 hours; or(93) between 5% and about 15% at 1 hour, between about 15% and about 25%at 2 hours, between about 20% and about 35% at 4 hours, between about25% and about 45% at 8 hours, between about 45% and about 60% at 12hours and between about 50% to about 60% at 16 hours; or (94) between15% and about 30% at 1 hour, between about 20% and about 40% at 2 hours,between about 20% and about 50% at 4 hours, between about 30% and about70% at 8 hours, between about 60% and about 80% at 12 hours and betweenabout 70% to about 90% at 16 hours; or (95) between 0% and about 50% at1 hour, between about 5% and about 50% at 2 hours, between about 5% andabout 70% at 4 hours, between about 10% and about 80% at 8 hours,between about 20% and about 100% at 12 hours and between about 40% toabout 100% at 16 hours; or (96) between 15% and about 40% at 1 hour,between about 15% and about 45% at 2 hours, between about 20% and about60% at 4 hours, between about 20% and about 80% at 8 hours, betweenabout 30% and about 90% at 12 hours and between about 40% to about 100%at 16 hours; or (97) between 0% to about 80% at 0.5 hours, and greaterthan about 40% at 1 hour; or (98) between 0% to about 40% at 0.5 hours,and greater than about 60% at 1 hour; or (98a) between 0% to about 20%at 0.5 hours, and greater than about 40% at 1 hour; or (99) between 0%to about 20% at 0.5 hours, and greater than about 20% at 1 hour; or(100) between 0% to about 90% at 0.5 hours, and greater than about 60%at 1 hour; or (101) between 0% to about 100% at 0.5 hours, and greaterthan about 60% at 1 hour; or (102) between 0% to about 90% at 1 hour,and greater than about 40% at 2 hours; or (103) between 0% to about 100%at 1 hour, and greater than about 60% at 2 hours; or (104) between 0% toabout 60% at 1 hour, and greater than about 40% at 2 hours; or (105)between 0% to about 40% at 1 hour, and greater than about 30% at 2hours; or (106) between 0% to about 50% at 1 hour, and greater thanabout 40% at 2 hours; or (107) between 0% to about 30% at 1 hour, andgreater than about 20% at 2 hours; or (108) between 0% and about 50% at1 hour, between about 0% and about 80% at 2 hours, between about 5% andabout 100% at 4 hours and between about 10% and about 100% at 8 hours;or (109) between 10% and about 60% at 1 hour, between about 15% andabout 75% at 2 hours, between about 20% and about 95% at 4 hours andbetween about 30% and about 100% at 8 hours; or (110) between 0% toabout 80% at 0.25 hours, and greater than about 90% at 1 hour; or (111)between 0% to about 100% at 0.25 hours, and greater than about 60% at 1hour. In some preferred embodiments, the foregoing in-vitro release rateof butorphanol is achieved when measured by the USP Basket or PaddleMethod at 100 rpm in 900 mL distilled water (time=0 hour begins here) at37° C. at any pH between 4.5 and 8 at 37° C., said release rate measuredfollowing dissolution (pretreatment) with USP Basket or Paddle Method at100 rpm in 900 mL of 0.1N HCl for two hours at 37° C., and thenfollowing further dissolution (pretreatment) with USP Basket or PaddleMethod at 100 rpm in 900 mL distilled water at any pH of between 2 and 4for a further time of up to two hours at 37° C. In some preferredembodiments, the foregoing dosage forms in (1) to (111) also incorporatea controlled release material and/or provide duodenal delivery, jejunaldelivery, ileal delivery, ileo-colonic delivery or colonic delivery. Insome preferred embodiments, the foregoing in-vitro release rate ofbutorphanol in (1) to (111) are achieved when measured by the USP Basketor Paddle Method at 100 rpm in 900 mL distilled water (time=0 hourbegins here) at 37° C. at a pH of between 4.5 and 8 at 37° C., saidrelease rate measured following dissolution (pretreatment) with USPBasket or Paddle Method at 100 rpm in 900 mL of 0.1N HCl for about 1,1.5 or 2 hours at 37° C. In some preferred embodiments, the foregoingin-vitro release rate of butorphanol in (1) to (111) are achieved whenmeasured by the USP Basket or Paddle Method at 100 rpm in 900 mLdistilled water (time=0 hour begins here) at 37° C. at a pH of between4.5 and 8 at 37° C., said release rate measured following dissolution(pretreatment) with USP Basket or Paddle Method at 100 rpm in 900 mL of0.1N HCl for about 1, 1.5 or 2 hours at 37° C., and then followingfurther dissolution (pretreatment) with USP Basket or Paddle Method at100 rpm in 900 mL distilled water at a pH of between 2 and 4 for afurther time of up to two hours at 37° C. In some preferred embodiments,the foregoing in-vitro release rate of butorphanol in (1) to (111) areachieved when measured by the USP Basket or Paddle Method at 100 rpm in900 mL distilled water at 37° C. at a pH of between 4.5 and 8 at 37° C.

In some more preferred embodiments, the dosage form for once-a-day orQ24H administration provides an oral modified release pharmaceuticalcomposition for the treatment of a butorphanol responsive medicalcondition comprising a therapeutically effective amount of butorphanolor pharmaceutically acceptable salts thereof or mixture thereof; andcontrolled release material to provide duodenal, jejunal or ilealrelease over an extended period of time, following dissolution(pretreatment) with USP Basket or Paddle Method at 100 rpm in 900 mL of0.1N HCl for two hours at 37° C., providing an in-vitro release rate byweight of butorphanol, when measured by the USP Basket or Paddle Methodat 100 rpm in 900 mL distilled water (time=0 hour begins here) at 37° C.at any pH between 4.5 and 8 at 37° C.: (1) between 0% to about 40% over0 to 4 hours, between about 10% to about 70% over 4 to 8 hours, betweenabout 40% to about 95% over 8 to 12 hours and more than 95% at 24 hours;(2) in some even more preferred embodiments, between 0% to about 30%over 0 to 4 hours, between about 15% to about 60% over 4 to 8 hours,between about 45% to about 90% over 8 to 12 hours and more than 70% at24 hours; (3) in some especially preferred embodiments, between 0% toabout 20% over 0 to 4 hours, between about 20% to about 50% over 4 to 8hours, between about 55% to about 85% over 8 to 12 hours and more than80% at 24 hours.

In some more preferred embodiments, the dosage form for once-a-day orQ24H administration provides an oral modified release pharmaceuticalcomposition for the treatment of a butorphanol responsive medicalcondition comprising a therapeutically effective amount of butorphanolor pharmaceutically acceptable salts thereof or mixture thereof; andcontrolled release material to provide duodenal, jejunal or ilealrelease over an extended period of time, following dissolution(pretreatment) with USP Basket or Paddle Method at 100 rpm in 900 mL of0.1N HCl for two hours at 37° C., providing an in-vitro release rate byweight of butorphanol, when measured by the USP Basket or Paddle Methodat 100 rpm in 900 mL distilled water (time=0 hour begins here) at 37° C.at any pH between 4.5 and 8 at 37° C.: (1) between 5% to about 20% at 1hour, between about 5% to about 40% at 4 hours, between about 20% toabout 70% at 9 hours, between about 30% to about 85% at 12 hours andmore than 60% at 24 hours; (2) in some even more preferred embodiments,between 10% to about 20% at 1 hour, between about 10% to about 40% at 4hours, between about 25% to about 65% at 9 hours, between about 35% toabout 75% at 12 hours and more than 70% at 24 hours; (3) in someespecially preferred embodiments, between 10% to about 15% at 1 hour,between about 15% to about 30% at 4 hours, between about 35% to about50% at 9 hours, between about 45% to about 65% at 12 hours and more than80% at 24 hours.

In some more preferred embodiments, the dosage form for once-a-day orQ24H administration provides an oral modified release pharmaceuticalcomposition for the treatment of a butorphanol responsive medicalcondition comprising a therapeutically effective amount of butorphanolor pharmaceutically acceptable salts thereof or mixture thereof; andcontrolled release material to provide duodenal, jejunal or ilealrelease over an extended period of time, providing an in-vitro releaserate by weight of butorphanol, when measured by the USP Basket or PaddleMethod at 100 rpm in 900 mL pH 6.8 phosphate buffer at 37° C. at 37° C.:(1) between 0% to about 40% over 0 to 4 hours, between about 10% toabout 70% over 4 to 8 hours, between about 40% to about 95% over 8 to 12hours and more than 95% at 24 hours; (2) in some even more preferredembodiments, between 0% to about 30% over 0 to 4 hours, between about15% to about 60% over 4 to 8 hours, between about 45% to about 90% over8 to 12 hours and more than 70% at 24 hours; (3) in some especiallypreferred embodiments, between 0% to about 20% over 0 to 4 hours,between about 20% to about 50% over 4 to 8 hours, between about 55% toabout 85% over 8 to 12 hours and more than 80% at 24 hours.

In some more preferred embodiments, the dosage form for once-a-day orQ24H administration provides an oral modified release pharmaceuticalcomposition for the treatment of a butorphanol responsive medicalcondition comprising a therapeutically effective amount of butorphanolor pharmaceutically acceptable salts thereof or mixture thereof; andcontrolled release material to provide duodenal, jejunal or ilealrelease over an extended period of time, providing an in-vitro releaserate by weight of butorphanol, when measured by the USP Basket or PaddleMethod at 100 rpm in 900 mL pH 6.8 phosphate buffer at 37° C. at 37° C.:(1) between 5% to about 20% at 1 hour, between about 5% to about 40% at4 hours, between about 20% to about 70% at 9 hours, between about 30% toabout 85% at 12 hours and more than 60% at 24 hours; (2) in some evenmore preferred embodiments, between 10% to about 20% at 1 hour, betweenabout 10% to about 40% at 4 hours, between about 25% to about 65% at 9hours, between about 35% to about 75% at 12 hours and more than 70% at24 hours; (3) in some especially preferred embodiments, between 10% toabout 15% at 1 hour, between about 15% to about 30% at 4 hours, betweenabout 35% to about 50% at 9 hours, between about 45% to about 65% at 12hours and more than 80% at 24 hours.

In some more preferred embodiments, the dosage form for twice-a-day orQ12H administration provides an oral modified release pharmaceuticalcomposition for the treatment of a butorphanol responsive medicalcondition comprising a therapeutically effective amount of butorphanolor pharmaceutically acceptable salts thereof or mixture thereof; andcontrolled release material to provide duodenal, jejunal or ilealrelease over an extended period of time, following dissolution(pretreatment) with USP Basket or Paddle Method at 100 rpm in 900 mL of0.1N HCl for two hours at 37° C., providing an in-vitro release rate byweight of butorphanol, when measured by the USP Basket or Paddle Methodat 100 rpm in 900 mL distilled water (time=0 hour begins here) at 37° C.at any pH between 4.5 and 8 at 37° C.: (1) between 0% to about 60% over0 to 4 hours, between about 20% to about 90% over 4 to 8 hours, betweenabout 30% to about 100% over 8 to 12 hours and more than 50% at 24hours; (2) in some even more preferred embodiments, between 0% to about50% over 0 to 4 hours, between about 30% to about 100% over 4 to 8hours, between about 40% to about 100% over 8 to 12 hours and more than60% at 24 hours; (3) in some especially preferred embodiments, between0% to about 40% over 0 to 4 hours, between about 40% to about 100% over4 to 8 hours, between about 50% to about 100% over 8 to 12 hours andmore than 90% at 24 hours.

In some more preferred embodiments, the dosage form for twice-a-day orQ12H administration provides an oral modified release pharmaceuticalcomposition for the treatment of a butorphanol responsive medicalcondition comprising a therapeutically effective amount of butorphanolor pharmaceutically acceptable salts thereof or mixture thereof; andcontrolled release material to provide duodenal, jejunal or ilealrelease over an extended period of time, following dissolution(pretreatment) with USP Basket or Paddle Method at 100 rpm in 900 mL of0.1N HCl for two hours at 37° C., providing an in-vitro release rate byweight of butorphanol, when measured by the USP Basket or Paddle Methodat 100 rpm in 900 mL distilled water (time=0 hour begins here) at 37° C.at any pH between 4.5 and 8 at 37° C.: (1) between 5% to about 50% at 1hour, between about 10% to about 80% at 4 hours, between about 20% toabout 100% at 9 hours, and more than about 40% at 12 hours; (2) in someeven more preferred embodiments, between 10% to about 40% at 1 hour,between about 15% to about 70% at 4 hours, between about 30% to about100% at 9 hours, and more than about 50% at 12 hours; (3) in someespecially preferred embodiments, between 15% to about 30% at 1 hour,between about 25% to about 60% at 4 hours, between about 65% to about100% at 9 hours, and more than about 80% at 12 hours.

In some more preferred embodiments, the dosage form for twice-a-day orQ12H administration provides an oral modified release pharmaceuticalcomposition for the treatment of a butorphanol responsive medicalcondition comprising a therapeutically effective amount of butorphanolor pharmaceutically acceptable salts thereof or mixture thereof; andcontrolled release material to provide duodenal, jejunal or ilealrelease over an extended period of time, providing an in-vitro releaserate by weight of butorphanol, when measured by the USP Basket or PaddleMethod at 100 rpm in 900 mL pH 6.8 phosphate buffer at 37° C. at 37° C.:(1) between 0% to about 60% over 0 to 4 hours, between about 20% toabout 90% over 4 to 8 hours, between about 30% to about 100% over 8 to12 hours and more than 50% at 24 hours; (2) in some even more preferredembodiments, between 0% to about 50% over 0 to 4 hours, between about30% to about 100% over 4 to 8 hours, between about 40% to about 100%over 8 to 12 hours and more than 60% at 24 hours; (3) in some especiallypreferred embodiments, between 0% to about 40% over 0 to 4 hours,between about 40% to about 100% over 4 to 8 hours, between about 50% toabout 100% over 8 to 12 hours and more than 90% at 24 hours.

In some more preferred embodiments, the dosage form for twice-a-day orQ12H administration provides an oral modified release pharmaceuticalcomposition for the treatment of a butorphanol responsive medicalcondition comprising a therapeutically effective amount of butorphanolor pharmaceutically acceptable salts thereof or mixture thereof; andcontrolled release material to provide duodenal, jejunal or ilealrelease over an extended period of time, providing an in-vitro releaserate by weight of butorphanol, when measured by the USP Basket or PaddleMethod at 100 rpm in 900 mL pH 6.8 phosphate buffer at 37° C. at 37° C.:(1) between 5% to about 50% at 1 hour, between about 10% to about 80% at4 hours, between about 20% to about 100% at 9 hours, and more than about40% at 12 hours; (2) in some even more preferred embodiments, between10% to about 40% at 1 hour, between about 15% to about 70% at 4 hours,between about 30% to about 100% at 9 hours, and more than about 50% at12 hours; (3) in some especially preferred embodiments, between 15% toabout 30% at 1 hour, between about 25% to about 60% at 4 hours, betweenabout 65% to about 100% at 9 hours, and more than about 80% at 12 hours.

Although dosage forms that provide pH independent in vitro dissolutionand in vivo release are frequently sought after and viewed favorably,particularly many controlled release or extended release forms, in someembodiments, pH independent dissolution and release can work against theobjectives of the some oral dosage forms of butorphanol (delayed onset,rapid release or delayed onset, extended release, or delayed onset,pulsatile release) which are intended to provide delivery or release ofthe dosage form in the proximal to the stomach, duodenum, or ileum(i.e., duodenal release, jejunal release, ileal release, ileo-colonicrelease or colonic release). Indeed, certain controlled release materialused to achieve delayed onset, duodenal release, jejunal release, ilealrelease, ileo-colonic release or colonic release exploit the pHdifference in the GI tract to achieve some or all of its objectives.

Therefore, in some preferred embodiments, where the oral butorphanolpharmaceutical composition is intended to provide delayed onset, rapidrelease or delayed onset, extended release, or delayed onset, pulsatilerelease through use of a pH sensitive controlled release material, thein-vitro release rate is substantially dependent on pH in that theamount of butorphanol released at an undesirable pH (e.g., pH 1.2) andthe amount released at a desirable pH (e.g., depending on the controlledrelease material and delivery and release objectives, pH 5.5, 6, 6.5, 7,7.2, 7.4), when measured in-vitro at 1.5 or 2 hours using the USP Basketor Paddle Method of USP Drug Release test of U.S. Pharmacopeia (2003) at100 rpm in 900 ml aqueous buffer is significantly different. Forexample, in some preferred embodiments, the in-vitro release ratedifference is greater than about 35%, or 40%, or 45%, or 50%, or 55%, or60% or 70%, or 80%, with the release rate higher at the desirable pHcompared with the undesirable pH.

In certain embodiments, the dosage forms of the invention contains oneor more substances in sufficient quantity to render said dosage formcontrolled release, such that: (i) in-vitro release rate of butorphanolby weight immediate release oral butorphanol compared with in-vitrorelease rate by weight of butorphanol from the dosage form of theinvention is at least about 10%, or at least about 15%, or at leastabout 20%, or at least about 30%, or at least about 40%, or at leastabout 50%, or at least about 60%, or at least about 70%, or at leastabout 80%, or at least about 90% faster, or at least 100% faster, or atleast 200% faster, or at least 300% faster, or at least 400% faster, orat least 500% faster, or at least 600% faster, or at least 700% faster,or at least 800% faster, or at least 1000% faster, at 0.25 hour, or at0.5 hours, or at 1 hour, or at 2 hours, or at 1 to 2 hours, whenmeasured by the USP Basket or Paddle Methods at 100 rpm in 900 mLaqueous buffer at a pH of between 1.6 and 7.2 at 37° C.; and/or (ii)in-vivo release rate of butorphanol by weight of any immediate releaseoral butorphanol compared with the in-vivo release rate of butorphanolfrom the dosage form of the invention is at least about 10%, or at leastabout 15%, or at least about 20%, or at least about 30%, or at leastabout 40%, or at least about 50%, or at least about 60%, or at leastabout 70%, or at least about 80%, or at least about 90% faster, or atleast 100% faster, or at least 200% faster, or at least 300% faster, orat least 400% faster, or at least 500% faster, or at least 600% faster,or at least 700% faster, or at least 800% faster, or at least 1000%faster, said in-vivo release rate quantified by the C_(max) ofbutorphanol after single dose administration to human subjects, eachdosage form administered according to its approved route ofadministration.

In some preferred embodiments, the oral dosage form is a controlledrelease material suitable for extended release oral administration to ahuman patient of the dosage form comprises a matrix. In some preferredembodiments, the said matrix is a plurality of multiparticulatematrices. In some preferred embodiments, the multiparticulates arecompressed into a tablet. In some preferred embodiments, themultiparticulates are disposed in a pharmaceutically acceptable capsule.

In some preferred embodiments, the in vivo pharmacokinetic parameters ofthe specifications and claims are derived or determined from firstadministration. In other preferred embodiments, the in vivopharmacokinetic parameters are derived or determined from steady stateadministration.

In some preferred embodiments, the in vivo pharmacokinetic parameters ofthe specifications and claims are derived or determined under fedconditions. In other preferred embodiments, the in vivo pharmacokineticparameters are derived or determined under fasted conditions.

In some preferred embodiments, the in vivo pharmacokinetic parameters ofthe specifications and claims are derived or determined from anindividual subject. In other preferred embodiments, the in vivopharmacokinetic parameters are derived or determined from a populationof subjects.

In some preferred embodiments, the in vivo specifications and claims ofthe invention are measured, reported, observed or achieved afteradministration of some or most doses of the invention. In otherpreferred embodiments, the in vivo specifications and claims of theinvention are measured, reported, observed or achieved afteradministration of substantially all or all doses of the invention.

In some preferred embodiments, the in vivo pharmacokinetic parameters ofthe specifications and claims are derived or determined in subjectshaving a Body Mass Index (BMI) between 18 and 26 kg/^(m2), inclusive(BMI=[weight in kg/height in ^(m2)]×10,000). In some preferredembodiments, the in vivo pharmacokinetic parameters of thespecifications and claims are derived or determined in subjects having aBody Mass Index (BMI)≧38 kg/^(m2).

Also disclosed are methods for the targeted release of butorphanol fromthe dosage form into the duodenum, jejunum, ileum and colon to provide atherapeutic effect comprising administering a therapeutically effectiveamount of oral butorphanol or a pharmaceutically acceptable salt ofbutorphanol or a mixture thereof.

Also disclosed are methods for the treatment of opioid dependence oraddiction disorders in a human patient suffering comprisingadministering a therapeutically effective amount of oral butorphanol ora pharmaceutically acceptable salt of butorphanol or a mixture thereof.Preferably, the addiction disorder is an opioid addiction disorder or apoly-substance abuse disorder.

Also disclosed are methods for resisting, deterring, minimizing orpreventing drug abuse, drug diversion and drug addiction in a humanpatient comprising administering a therapeutically effective amount oforal butorphanol or a pharmaceutically acceptable salt of butorphanol ora mixture thereof.

Also disclosed are methods for the treatment of medical conditionsamenable to treatment with butorphanol in patients who are at higherrisk for nausea, vomiting, sedation or other opioid agonist side effectsor who have a prior history of said side effects on other opioidscomprising administering a therapeutically effective amount of oralbutorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof.

Also disclosed are methods for the treatment of medical conditionsamenable to treatment with butorphanol in patients who are at higherrisk for nausea, vomiting, sedation or other side effects withintranasal butorphanol oral immediate release butorphanol comprisingadministering a therapeutically effective amount of oral butorphanol ora pharmaceutically acceptable salt of butorphanol or a mixture thereof.

Also disclosed are methods for the treatment of dyspnea, cough and COPDcomprising administering a therapeutically effective amount of oralbutorphanol or a pharmaceutically acceptable salt of butorphanol or amixture thereof.

Also disclosed are methods for the treatment of medical conditionsamenable to treatment with butorphanol or opioid agonists in a humanpatient who also suffers from an addiction disorder, who is at risk orincreased risk for addiction or who may be prone to drug diversion intoillicit channels comprising administering a therapeutically effectiveamount of oral butorphanol or a pharmaceutically acceptable salt ofbutorphanol or a mixture thereof.

Also disclosed are methods for the treatment of medical conditionsamenable to treatment with butorphanol or opioid agonists in a humanpatient suffering comprising administering a therapeutically effectiveamount of oral butorphanol or a pharmaceutically acceptable salt ofbutorphanol or a mixture thereof.

Also disclosed are methods for preventing and treating pain in a humanpatient comprising administering a therapeutically effective amount oforal butorphanol or a pharmaceutically acceptable salt of butorphanol ora mixture thereof.

All pain states are contemplated by this invention, regardless ofetiology, mechanisms, duration, prior treatment response and anatomiclocation, including acute pain, inflammatory pain, chronic pain, cancerpain, visceral pain and neuropathic pain.

Also disclosed are methods of providing relief in a human patientsuffering from neuropathic and chronic pain comprising a therapeuticallyeffective amount of oral butorphanol or a pharmaceutically acceptablesalt butorphanol or a mixture thereof. In some preferred embodiments,the dosage form of the invention is intended for the treatment ofneuropathic pain, peripheral neuropathic pain, central neuropathic pain,chronic pain, osteoarthritis, back pain, cancer pain, and chronicinflammatory pain.

Also disclosed are methods of providing relief in a human patientsuffering from acute pain comprising a therapeutically effective amountof oral butorphanol or a pharmaceutically acceptable salt butorphanol ora mixture thereof.

Also disclosed are methods of providing relief in a human patientsuffering from an addiction disorder comprising a therapeuticallyeffective amount of oral butorphanol or a pharmaceutically acceptablesalt butorphanol or a mixture thereof.

All kinds of kits of the present invention are contemplated. In somepreferred embodiments, also provided are kits for use in treating orpreventing the pain with the oral administration of butorphanol or apharmaceutically acceptable salt of butorphanol, or a mixture thereoffor a subject in need of such treatment, comprising: (i) a dosage formof the invention; (ii) a container for the dosage form; and optionally,any of (iii) to (vi): (iii) a container for individual units of thedosage form (e.g., individual tablets or capsules in blisters); (iv)educational instructions in any media about various medical conditions,their etiology, pathophysiology, consequences and treatment, includinginformation on the potential for abuse and diversion and methods forprevention of same and information on the proper use and disposal of themedication; (v) containers or bags for the safe disposal of any used orremaining unused dosage form, preferably child proof and flushable; (vi)tamper evident and child proof packaging for the kit and its contents.

The amount of butorphanol in the oral dosage form will vary depending onvariety of physiologic, pharmacologic, pharmacokinetic, pharmaceuticaland physicochemical factors, including: (i) the choice of butorphanol asthe base, pharmaceutically acceptable salt or mixtures thereof; (ii) thenature of the oral dosage form (e.g., immediate release or extendedrelease); (iii) the anatomical location of the pain relieving target;(iv) the intensity and intractability of the pain; (v) the contributionof different mechanism to the initiation, propagation, summation andmaintenance of the pain; (vi) the absorption, metabolism, distributionand excretion of orally administered butorphanol in healthy subjects andin patients with various diseases and disorders, including renal andhepatic impairment; (vii) the presence of comorbid pathology; (viii) thepatient's risk of iatrogenic side effects; (ix) the tolerability of thedose, including the patient's propensity for butorphanol associated CNSand gastrointestinal side effects; (x) use of concurrent analgesics;(xi) the efficiency of the dosage form.

In certain embodiments, the amount of butorphanol in the dosage form isabout 0.001 mg to 1500 mg. In other embodiments, the amount ofbutorphanol in the dosage form is about 0.1 mg to 1000 mg. In otherembodiments, the amount of butorphanol in the dosage form is about 0.5mg to about 500 mg or about 1 mg to about 200 mg, or 2 mg to about 100mg or 1 mg to about 60 mg. In certain embodiments, the maximum dose oforal butorphanol exceeds the maximum approved dose of intranasalbutorphanol by at least about 5%, or 10%, or 15%, or 20%, or 30%, or40%, or 50%, or 60%, or 70%, or 80%, or 90%, or 100%, or 120%, or 140%,or 160%, or 180%, or 200%, or 220%, or 240%, or 260%, or 280%, or 300%,or 320%, or 340%, or 360%, or 380%, or 400%, or 450%, or 500%, or 550%,or 600%, or 650%, or 700%. In certain embodiments, the minimum dose oforal butorphanol exceeds the minimum approved dose of intranasalbutorphanol by at least about 5%, or 10%, or 15%, or 20%, or 30%, or40%, or 50%, or 60%, or 70%, or 80%, or 90%, or 100%, or 120%, or 140%,or 160%, or 180%, or 200%, or 220%, or 240%, or 260%, or 280%, or 300%,or 320%, or 340%, or 360%, or 380%, or 400%, or 450%, or 500%, or 550%,or 600%, or 650%, or 700%. In certain embodiments, the average dose oforal butorphanol exceeds the average dose of intranasal butorphanol byat least about 5%, or 10%, or 15%, or 20%, or 30%, or 40%, or 50%, or60%, or 70%, or 80%, or 90%, or 100%, or 120%, or 140%, or 160%, or180%, or 200%, or 220%, or 240%, or 260%, or 280%, or 300%, or 320%, or340%, or 360%, or 380%, or 400%, or 450%, or 500%, or 550%, or 600%, or650%, or 700%. In certain embodiments, the induction (where appropriate)or maintenance dose of oral butorphanol exceeds the approved induction(where appropriate) or maintenance dose of intranasal butorphanol by atleast about 5%, or 10%, or 15%, or 20%, or 30%, or 40%, or 50%, or 60%,or 70%, or 80%, or 90%, or 100%, or 120%, or 140%, or 160%, or 180%, or200%, or 220%, or 240%, or 260%, or 280%, or 300%, or 320%, or 340%, or360%, or 380%, or 400%, or 450%, or 500%, or 550%, or 600%, or 650%, or700%. In certain embodiments, the induction (where appropriate) dose,maintenance dose, minimum dose, average doe and/or maximum dose of oralbutorphanol exceeds the corresponding dose intranasal butorphanol by atleast about 5%, or 10%, or 15%, or 20%, or 30%, or 40%, or 50%, or 60%,or 70%, or 80%, or 90%, or 100%, or 120%, or 140%, or 160%, or 180%, or200%, or 220%, or 240%, or 260%, or 280%, or 300%, or 320%, or 340%, or360%, or 380%, or 400%, or 450%, or 500%, or 550%, or 600%, or 650%, or700%. In certain embodiments, the dose of oral butorphanol is at leastabout 2 mg, or 3 mg, or 4 mg, or 5 mg, or 6 mg, or 7 mg, or 8 mg, or 9mg, or 10 mg or 11 mg, or 12 mg, or 13 mg, or 14 mg, or 15 mg, or 16 mg,or 17 mg, or 18 mg, or 19 mg, or 20 mg, or 21 mg, or 22 mg, or 23 mg, or24 mg, or 25 mg, or 26 mg, or 27 mg, or 28 mg, or 29 mg, or 30 mg, or 32mg, or 34 mg, or 35 mg, or 36 mg, or 38 mg, or 40 mg, or 45 mg, or 50mg, or 55 mg, or 60 mg, or 65 mg, or 70 mg. In certain embodiments, theamount of butorphanol base in the dosage form is not less than 10 mg, ornot less than about 10 mg, or 11 mg, or 12 mg, or 13 mg or 14 mg, or 15mg, or 16 mg, or 17 mg, or 18 mg, or 19 mg, or 20 mg, or 21 mg, or 22mg, or 23 mg, or 24 mg, or 25 mg, or 26 mg, or 27 mg, or 28 mg, or 29mg, or 30 mg. In certain embodiments, the amount of butorphanolhydrochloride in the dosage form is not less than 10 mg, or not lessthan about 10 mg, or 11 mg, or 12 mg, or 13 mg or 14 mg, or 15 mg, or 16mg, or 17 mg, or 18 mg, or 19 mg, or 20 mg, or 21 mg, or 22 mg, or 23mg, or 24 mg, or 25 mg, or 26 mg, or 27 mg, or 28 mg, or 29 mg, or 30mg. In certain embodiments, the amount of any pharmaceuticallyacceptable salt of butorphanol in the dosage form is not less than 10mg, or not less than about 10 mg, or 11 mg, or 12 mg, or 13 mg or 14 mg,or 15 mg, or 16 mg, or 17 mg, or 18 mg, or 19 mg, or 20 mg, or 21 mg, or22 mg, or 23 mg, or 24 mg, or 25 mg, or 26 mg, or 27 mg, or 28 mg, or 29mg, or 30 mg. In certain embodiments, the daily dose of butorphanol orits pharmaceutically acceptable salt in the dosage form is not less than40 mg, or 50 mg or 60 mg or 65 mg.

The invention is also directed to methods of preparing the dosage formsdisclosed herein.

The invention is also directed to a process for the preparation andmanufacture of the dosage form.

The invention is also directed to methods of treating butorphanolresponsive medical conditions comprising administering a therapeuticallyeffective amount of oral butorphanol in a dosage form of the invention,or pharmaceutically acceptable salts thereof or mixtures thereof.

The invention is also directed to methods of treating pain, chronicpain, neuropathic pain, opioid dependence, dyspnea, cough and addictiondisorders comprising administering a therapeutically effective amount oforal butorphanol in a dosage form of the invention, or pharmaceuticallyacceptable salts thereof or mixtures thereof.

The invention is also directed to methods of treating butorphanolresponsive medical conditions with reduced risk of drug abuse, drugmisuse, and drug diversion comprising administering a therapeuticallyeffective amount of oral butorphanol in a dosage form of the invention,or pharmaceutically acceptable salts thereof or mixtures thereof.

The invention is also directed to methods of improving treatmentcompliance and deter episodic, occasional, intermittent, periodic, asneeded, or PRN use of the dosage form when treating butorphanolresponsive medical conditions requiring more than few days of therapy tomore than a few weeks of therapy or chronic therapy comprisingadministering a therapeutically effective amount of oral butorphanol ina dosage form of the invention, or pharmaceutically acceptable saltsthereof or mixtures thereof.

In certain preferred embodiments, the butorphanol in the dosage form iscombined with one or more other drugs for the treatment of the samemedical condition as the butorphanol or for the treatment of a differentmedical condition. All modes of co-administration are contemplated,including via an oral, subcutaneous, direct intravenous, slowintravenous infusion, continuous intravenous infusion, intravenous orepidural patient controlled analgesia (PCA and PCEA), intramuscular,intrathecal, epidural, intracisternal, intramuscular, intraperitoneal,transdermal, topical, transmucosal, buccal, sublingual, inhalation,intranasal, epidural, intra-atricular, intranasal, rectal or ocularroutes.

The term “first administration” means administration of a dose of thepresent invention at the initiation of therapy to an individual patientor a patient population.

The term “steady state” means that the amount of the drug reaching thesystem is approximately the same as the amount of the drug leaving thesystem. Thus, at “steady-state”, the patient's body eliminates the drugat approximately the same rate that the drug becomes available to thepatient's system through absorption into the blood stream.

As used herein the terms: (i) “AUC₀₋₄”, and “AUC_(0-τ)” (or“AUC_(0-Tau)”) mean the area under the plasma drug concentration-timecurve from time zero to the intended dosing frequency of the dosage formafter a single administration (e.g., 8 hours, 12 hours or 24 hours) andto the end of the dosing interval after repeated dosing or atsteady-state, respectively; (ii) “AUC_(0-inf)” (means area under theplasma drug concentration-time curve from time zero to infinity; (iii)“AUC₀₋₆” means area under the plasma drug concentration-time curve fromtime zero to 6 hours after dosing; (iv) “AUC₀₋₈” means area under theplasma drug concentration-time curve from time zero to 8 hours afterdosing; (v) “AUC₀₋₁₂” means area under the plasma drugconcentration-time curve from time zero to 12 hours after dosing; (vi)“AUC₀₋₂₄” means area under the plasma drug concentration-time curve fromtime zero to 24 hours after dosing; (vii) “C_(max)” means the maximumobserved plasma drug concentration; (viii) “C₆” means the plasma drugconcentration at 6 hours after dosing; (ix) “C₈” means the plasma drugconcentration at 8 hours after dosing; (x) “C₁₂” means the plasma drugconcentration at 12 hours after dosing; (xi) “C₂₄” means the plasma drugconcentration at 24 hours after dosing; (xii) “t_(max)” or “T_(max)”means the time of the observed maximum drug concentration (also known astime to achieve C_(max)); (xiii) “C_(min)” means the minimum observeddrug concentration following the maximum plasma concentration or theconcentration at the end of the intended dosing interval; (xiv) “halfvalue duration” or “HVD” means the duration over the dosing intervalduring which plasma concentration of drug are greater than or equal toone-half of C_(max), obtained by calculating the time interval beginningwhen the interpolated concentration first equals or exceeds one-half ofC_(max) and ending at the first time point for which the interpolatedconcentration falls below one-half of C_(max); (xv) “W₅₀” for purposesof the present invention means the width of the plasma concentrationtime curve at 50% of the height of the C_(max) over the dosing interval;(xvi) “steady state” is a state of equilibrium wherein the amount of thedrug reaching the system is approximately the same as the amount of thedrug leaving the system or put another way, the patient's bodyeliminates the drug at approximately the same rate that the drug becomesavailable to the patient's system through absorption into the bloodstream, said “time to steady state” measured by calculating the C_(min)after each sequential dosing of drug administered at the intended dosingfrequency until two consecutive C_(max)'s are not statisticallydifferent at a 10% significance level (p=0.10); (xvii) “percentfluctuation” means the variation in plasma concentrations of the drugcomputed as: (a) (C_(max)−C_(min))/C_(min)×100 (for an individualpatient) and (mean C_(max)−mean C_(min))/mean C_(av)×100 (for apopulation); or (b) (C_(max)−C_(min))/C_(av)×100 (for an individualpatient) and (mean C_(max)−mean C_(min))/mean C_(av)×100 (for apopulation); (xviii) “accumulation index” or “AI” means the ratio of theplasma concentration of the drug at the end of the intended dosinginterval (i.e., 8 hours for a Q8H dosage form, 12 hours for a Q12Hdosage form, and 24 hours for a Q24H dosage form) after administration,determined at steady-state (C_(ssmin)) to the plasma concentration ofthe drug at the end of the intended dosing interval determined at firstadministration (i.e., after the first dose); (xix) “AUC_(0-n)” means thearea under the plasma drug concentration-time curve from time zero tothe specified time point (“n).

Pharmacokinetic parameters of the invention are be computed from singledose (i.e., first administration) and steady state pharmacokineticstudies conducted in an individual subject or in a population ofsubjects in the fasted or fed states. The AI and percent of steady statecomputations requires both single dose (i.e., first administration) andsteady state pharmacokinetic assessment.

In certain preferred embodiments of the present invention, an effectiveamount of butorphanol in immediate release form is included in thecontrolled release unit dose butorphanol formulation to be administered.The immediate release form of the butorphanol is preferably included inan amount which is effective to shorten the time to C_(max) of thebutorphanol in the blood (e.g., plasma). In such embodiments, aneffective amount of the butorphanol in immediate release form may becoated onto the substrates of the present invention. For example, wherethe extended release butorphanol from the formulation is due to acontrolled release coating, the immediate release layer would beovercoated on top of the controlled release coating. On the other hand,the immediate release layer maybe coated onto the surface of substrateswherein the butorphanol is incorporated in a controlled release matrix.Where a plurality of the sustained release substrates comprising aneffective unit dose of the butorphanol (e.g., multiparticulate systemsincluding pellets, spheres, beads and the like) are incorporated into ahard gelatin capsule, the immediate release portion of the butorphanoldose may be incorporated into the gelatin capsule via inclusion of thesufficient amount of immediate release butorphanol as a powder orgranulate within the capsule. Alternatively, the gelatin capsule itselfmay be coated with an immediate release layer of the butorphanol. Oneskilled in the art would recognize still other alternative manners ofincorporating the immediate release butorphanol into the unit dose. Suchalternatives are deemed to be encompassed by the appended claims. Byincluding such an effective amount of immediate release butorphanol inthe unit dose, the experience of relatively higher levels of pain inpatients may be significantly reduced.

For purposes of the invention, the term “a patient” in reference topharmacokinetic parameters means that the discussion (or claim) isdirected to the pharmacokinetic parameters of an individual patient orsubject.

The term “population of patients” or “patient population” means that thediscussion (or claim) is directed to the mean pharmacokinetic parametersof at least two patients or subjects.

In certain preferred embodiments, any one or all of the above in-vivoparameters are achieved after a first administration (often referred toas “single dose administration”) of the dosage form to a human patientor a population of human patients.

In certain alternative embodiments, any one or all of the above in-vivoparameters are achieved after steady state administration of the dosageform to a human patient or a population of human patients.

The term “USP Paddle or Basket Method” is the Paddle and Basket Methoddescribed, e.g., in specified in the United States Pharmacopeia, USP-28NF-23 (2005), published by the United States Pharmacopeial Convention,Inc, herein incorporated by reference.

The term “pH-dependent” for purposes of the present invention is definedas having characteristics (e.g., dissolution) which vary according toenvironmental pH.

The term “pH-independent” for purposes of the present invention isdefined as having characteristics (e.g., dissolution) which aresubstantially unaffected by pH.

The term “pH-dependent” for purposes of the present invention is definedas having characteristics (e.g., dissolution) which are substantiallyaffected by pH.

The term “bioavailability” is defined for purposes of the presentinvention as the extent to which the drug (e.g., butorphanol) isabsorbed from the unit dosage forms.

All oral pharmaceutical dosage forms of the invention are contemplated,including oral suspensions, tablets, capsules, effervescent tablets,effervescent powders, powders, solutions, powders for reconstitution,oral gastroretentive tablets and capsules, administered as immediaterelease, modified release, enteric coated, sustained release, controlledrelease, pulsatile release and extended release dosage form.

In some preferred embodiments of the invention, the dosage formcomprises one or more of the following: modified release or entericcoated or sustained release or controlled release or pulsatile releaseor extended release. In some preferred embodiments of the invention, thedosage form comprises only one of the following: modified release orenteric coated or sustained release or controlled release or pulsatilerelease or extended release. In some preferred embodiments of theinvention, the dosage form specifically excludes delayed onset, rapidrelease dosage forms. In some preferred embodiments of the invention,the dosage form specifically excludes delayed onset, extended releasedosage forms

In some embodiments, the invention specifically excludes oral immediaterelease dosage forms.

In some preferred embodiments of the invention, the dosage form of theinvention is controlled release, extended release, sustained release,modified release, or delayed onset.

In some preferred embodiments of the invention, the dosage form of theinvention is delayed onset, rapid release or delayed onset, extendedrelease, or delayed onset, pulsatile release.

In some preferred embodiments of the invention, the dosage form of theinvention is delayed onset, duodenal delivery, jejunal delivery, ilealdelivery, ileo-colonic delivery, colonic delivery

In some embodiments, the controlled release material of the dosage formmay function to provide duodenal delivery, jejunal delivery, ilealdelivery, ileo-colonic delivery or colonic delivery.

In some embodiments, the controlled release material of the dosage formmay function to provide delayed onset, rapid release or delayed onset,extended release, or delayed onset, pulsatile release

In some preferred dosage forms of the invention, the dosage formincludes taste aversive agents (e.g., bittering agents) in sequesteredor unsequestered form to deter sublingual, oromucosal, buccal orintranasal use of the dosage form. In some embodiments, the tasteaversive agents (bittering agent) is coated on the oral dosage form andthen overcoated with material which prevents or minimizes the bittersensation upon normal oral ingestion but which does not protect againstan aversive taste upon prolonged residence in the oral cavity (e.g.,upon sublingual, oromucosal or buccal use) or upon intranasal use. Inthis manner the taste aversive agent is not sequestered in the sensethat it is readily released in the GI tract upon oral ingestion, whereit is devoid of taste aversive effects. A wide variety of pharmaceuticalexcipients known in the art may be used to provide the desired outercoating to the dosage form. In some embodiments, the taste aversiveagents (e.g., bittering agent) is incorporated in the oral dosage formwhich prevents or minimizes the bitter sensation upon normal oralingestion but which does not protect against an aversive taste uponprolonged residence in the oral cavity (e.g., upon sublingual,oromucosal or buccal use). In this manner the taste aversive agent maybe sequestered or unsequestered. In some embodiments, the taste aversiveagents (e.g., bittering agent) is incorporated into the inside walls ofthe capsule shell which prevents or minimizes the bitter sensation uponnormal oral ingestion but which does not protect against an aversivetaste upon prolonged residence in the oral cavity (e.g., uponsublingual, oromucosal or buccal use).

In some preferred embodiments, the dosage form is non-releasable orsubstantially non-releasable until (i) after a particular time followingoral ingestion, when the dosage form can be anticipated to have reachedthe duodenum, jejum, ileum, ileo-cecal junction, cecum, or colon; (ii)the dosage form has come in contact or substantial contact or sustainedcontact with a desired gastrointestinal pH environment (e.g., pH>3, orpH>3.5, or pH>4, or pH>4.5, or pH, >5, or pH>5.5, or pH>6, or pH>7, orpH>7.5, or pH>7.8); (iii) the dosage form has come in contact withdesired microbial flora (e.g., colonic microbial flora).

In certain situations involving pharmacokinetic evaluations, it may notbe possible to provide the same amount of drug by different routes ofadministration due to the lack of commercially available dosagestrengths or because such administration would require testing outsidethe approved method of administration (e.g., simultaneous intranasaladministration of more than one or two doses into each nostril of oraladministration of high doses of immediate release butorphanol). Undersuch circumstances, the term “after the same amount of an oral immediaterelease formulation of butorphanol” and after the same amount of anintranasal formulation of butorphanol” may be waived and differentamounts of drug may be evaluated, provided the data are dose normalizedusing pharmacokinetic approaches well known in the art.

The term “agonist” means a ligand that binds to a receptor and altersthe receptor state resulting in a biological response. Conventionalagonists increase receptor activity, whereas inverse agonists reduce it(See Neubig et al, IUPHAR Committee on Receptor Nomenclature andClassification, Pharmacol Rev, 2003; Howlett et al., Mol Pharmacol,1988).

The term “opioid agonist” means a molecule that causes a specificphysiologic, pathophysiologic or pharmacologic effect after binding toan opioid receptor.

An “antagonist” is a drug or ligand that reduces the action of anotherdrug or ligand, generally an agonist. Many antagonists act at the samereceptor macromolecule as the agonist. (See Neubig et al, IUPHARCommittee on Receptor Nomenclature and Classification, Pharmacol Rev,2003; Howlett et al., Mol Pharmacol, 1988).

The term “receptor” means a molecule within a cell, on a cell surface,on a membrane, in tissue, in fluid or otherwise found in humans thatserve as a recognition or binding site to cause specific physiologic,pathophysiologic or pharmacologic effects. The term “receptor” alsomeans a cellular macromolecule, or an assembly of macromolecules, thatis concerned directly and specifically in chemical signaling between andwithin cells. Combination of a hormone, neurotransmitter, drug, ligand,or intracellular messenger with its receptor(s) initiates a change incell function (Neubig et al, IUPHAR Committee on Receptor Nomenclatureand Classification, Pharmacol Rev, 2003).

The term “opioid receptor” includes mu (μ), delta (δ) and kappa (κ)opioid receptors, their subtypes and splice variants such as mu₁, mu₂,delta₁, delta₂, kappa₁, kappa₂ and kappa₃, etc.

Opioid antagonists are known or readily determined by individuals whopractice the art. Preferably, the opioid antagonists useful for thepresent invention may be selected from the group consisting ofnaltrexone, methylnaltrexone, nalbuphine, naloxone, nalmefene,cyclazocine, cyclorphan, oxilorphan nalorphine, nalorphine dinicotinate,nalmefene, nadide and levallorphan.

In certain preferred embodiments of the present invention, the inventionallows for the use of lower doses of butorphanol by virtue of theinclusion or co-administration of an additional drug for the preventionor treatment of pain. By using lower amounts of either or both drugs,the side effects associated with treatment in humans are reduced.

The term “(−)17-(cyclobutylmethyl)morphinan-3,14-diol” is usedinterchangeably with “butorphanol”,(−)-17-(cyclobutylmethyl)morphinan-3, and 14-diol,17-cyclobutylmethylmorphinan-3,14-diol and means butorphanol base (CASnumber 42408-82-2), as well as their pharmaceutically acceptable salts,prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs,and hydrates, as racemates or an individual diastereoisomers orenantiomeric isomers thereof or mixtures thereof. In some preferredembodiments, the pharmaceutically acceptable salt is the tartrate(butorphanol tartrate CAS number 58786-99-5). In other preferredembodiments, the dosage form comprises butorphanol base. In some evenmore preferred embodiments, the dosage form comprises butorphanoltartrate or butorphanol, or mixtures thereof.

The phrase “comprising a therapeutically effective amount ofbutorphanol” means “comprising a therapeutically effective amount ofbutorphanol or a pharmaceutically acceptable salt of butorphanol, orprodrugs, esters, analogs, derivatives, solvates, complexes, polymorphsand hydrates thereof, as racemates or an individual diastereoisomers orenantiomeric isomers thereof or mixtures thereof.

When the dosage form includes a pharmaceutically acceptable salt, anysalt may be use. Preferably, the salt is the hydrochloride salt ofbutorphanol.

The singular forms “a”, “an” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a polymer” includes a single polymer as well as a mixture of two ormore different polymers, reference to “a permeation enhancer” includes asingle permeation enhancer as well as two or more different permeationenhancer in combination, and the like.

Some of the drugs disclosed herein may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. The present invention is also meant to encompassall such possible forms as well as their racemic and resolved forms andmixtures thereof. When the compounds described herein contain olefinicdouble bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended to include both E and Z geometricisomers. All tautomers are intended to be encompassed by the presentinvention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms is space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image rotates the plane of polarized light inthe opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The mean drowsiness score is the score in mm on a 100 mm VAS scalebounded on the left by “no drowsiness” and on the right by “extremedrowsiness”.

The mean nausea score is the score in mm on a 100 mm VAS scale boundedon the left by “no nausea” and on the right by “extreme nausea”.

The mean dizziness score is the score in mm on a 100 mm VAS scalebounded on the left by “no dizziness” and on the right by “extremedizziness”.

The mean vomiting score is the number of episodes of vomiting orretching.

The “NNH” or “number needed to harm” is a measure that indicates howmany patients would require a specific treatment to cause harm in onepatient. As used herein, the “NNH or “number needed to harm” is ameasure that includes: (i) how many opioid naïve healthy subjects wouldrequire treatment to cause moderate or severe sedation (or drowsiness)in one subject, where moderate to severe sedation or drowsiness isdefined as a VAS score of ≧50 mm on a 100 mm scale bounded on the leftby “no sedation or drowsiness” and on the right by “extreme sedation ordrowsiness”; (ii) how many opioid naïve healthy subjects would requiretreatment to cause moderate or severe nausea in one subject, wheremoderate to severe nausea is defined as a VAS score of ≧50 mm on a 100mm scale bounded on the left by “no nausea” and on the right by “extremenausea”; (iii) how many opioid naïve healthy subjects would requiretreatment to cause dizziness in one subject, where dizziness is definedas unsteadiness, imbalance, lightheadedness, spinning sensation orsensation that one is falling.

The “drug effects” questionnaire assesses the extent to which subjectscurrently felt a drug effect, on a scale of 1 to 5 (1=“I feel no effectfrom it at all”; 2=“I think I feel a mild effect, but I'm not sure”;3=“I feel an effect, but it is not real strong”; 4=“I feel a strongeffect”; 5=“I feel a very strong effect”). This questionnaire can beused to examine the overall drug effects, preferably in drug abusers andrecreational drug users.

The “drug liking” questionnaire assesses the extent to which subjectscurrently like the effects of the drug on a 100-mm VAS, bounded on theleft by “0=dislike a lot”, bounded on the right by “100=like a lot”.This questionnaire can be used to examine the overall drug liking of,preferably in drug abusers and recreational drug users.

The “take again” questionnaire assesses whether subjects would take thedrug again if given the opportunity. The patient is asked “If given anopportunity, would you take this drug again? (circle one: YES or NO).This questionnaire can be used to examine the overall desirability ofthe drug experience, preferably in drug abusers and recreational drugusers.

On the “coasting” questionnaire the patient is asked to put a mark on ahorizontal line that best describes their response to the question: “Doyou feel like you are coasting or spaced out? The horizontal line is avisual analog scale (VAS) bounded on the left by “not at all” and on theright by “extremely”. This questionnaire can be used to examine thedegree to which subjects feel like they are coasting or spaced out,preferably in drug abusers and recreational drug users.

Three performance tasks may be employed for measuring skills related todriving.

The “critical tracking task” measures the patient's ability to control adisplayed error signal in a first-order compensatory tracking task. Theerror is displayed as a horizontal deviation of a cursor from themidpoint on a horizontal, linear scale. Compensatory joystick movementscorrect the error by returning the cursor to the midpoint. The frequencyat which the patient loses the control is the critical frequency. Thecritical tracking task measures the psychomotor control during a closedloop operation. It is a laboratory analog to on-the-road trackingperformance.

The “stop signal task” measures motor impulsivity, which is defined asthe inability to inhibit an activated or pre-cued response leading toerrors of commission. The task requires patients to make quick keyresponses to visual go signals, i.e. the letters ABCD presented one at atime in the middle of the screen, and to inhibit any response when avisual stop signal, i.e. “*” in one of the four corners of the screen,is presented at predefined delays. The main dependent variable is thestop reaction time on stop signal trials that represents the estimatedmean time required to inhibit a response.

The “Tower of London” (TOL) is a decision-making task that measuresexecutive function and planning. The task consists of computer generatedimages of begin- and end-arrangements of three colored balls on threesticks. The subject's task is to determine as quickly as possible,whether the end-arrangement can be accomplished by “moving” the balls intwo to five steps from the beginning arrangement by pushing thecorresponding number coded button. The total number of correct decisionsis the main performance measure.

In some embodiments, the dosage form of the invention, one or more orall of the specifications and claims applicable to the prevention andtreatment of pain or addiction disorders is also applicable to theprevention or treatment of any other disease or disorder that respondsto opioid agonists or to butorphanol.

The prevention and treatment of all diseases and disorders iscontemplated by the use of this invention, including without limitation,(i) pain; (ii) addiction disorders; (iii) opioid substitution and opioidmaintenance therapy; (iv) restless leg syndrome; (v) cough; (vi) urinaryincontinence; (vii) cough; (viii) pain associated with sickle celldisease, including vaso-occlusive crisis; (ix) peripheral and centralneuropathic pain; (x) cancer pain; (xi) breakthrough pain; (xii)visceral pain; (xiii) dyspnea and respiratory distress; (xiv)infectious, immunologic, cardiovascular, pulmonary, gastrointestinal,hepatic, biliary, nutritional, metabolic, endocrine, hematologic,oncologic, musculoskeletal, rheumatic, neurologic, psychiatric,genitourinary, gynecologic, obstetric, pediatric, otolaryngogologic,ophthalmic, dermatologic, dental, oral, and genetic disorders, diseasesand maladies and signs and symptoms thereof; (xv) depression,schizophrenia, influenza, common colds, anxiety, panic attacks,agoraphobia, ADHD, insomnia, sleep disorders, nasal congestion,headaches, migraine, urinary incontinence, constipation, allergies,cough, pneumonia, COPD, asthma, fluid retention, acid reflux, pepticulcers, hypertension, cardiac arrhythmias, hypercholesterolemia, CHF,fever, diarrhea, back pain, myofascial pain, osteoarthritis, neuropathicpain, cancer pain, acute pain, diabetes, muscle spasms, and rheumatoidarthritis, and signs and symptoms thereof; and (xvi) disorders, diseasesand maladies, and signs and symptoms thereof referred to in Harrison'sPrinciples of Internal Medicine, 16th Edition, 2004, Kasper D L,Braunwald W, Fauci A, Hauser S, Longo D, and Jameson J L (eds)], whichis hereby incorporated in its entirety by reference; said disorders,diseases and maladies, and signs and symptoms thereof comprisingbutorphanol responsive medical conditions.

In some preferred embodiments, the oral pharmaceutical dosage forms ofbutorphanol are used to treat pain, sickle cell disease pain, cough,dyspnea, opioid addiction disorders, restless leg syndrome,fibromylagia, acute herpes zoster, visceral pain, breakthrough pain,opioid dependence and urinary incontinence.

As used herein, “pruritus” means an unpleasant sensation that evokes thedesire or reflex to scratch the skin. Pruritus includes, but is notlimited to idiopathic itch, iatrogenic itch (e.g., cutaneousmanifestations of drug reactions), neurogenic itch secondary to skindisorders (e.g., inflammation, dryness, atopic dermatitis, scabies,urticaria, and insect bite reactions), itch secondary to systemicdisorders (e.g., chronic liver disease or chronic renal failure),neuropathic itch (e.g., herpes zoster, postherpetic neuropathy, notalgiaparesthetica, multiple sclerosis and brain tumors) and psychogenic itch(e.g., parasitophobia and obsessive compulsive disorder).

As used herein, “cough” includes acute cough, chronic cough, iatrogeniccough, post-infectious cough, and cough secondary to asthma, COPD, lungcancer, gastroesophageal reflux disease, respiratory bacterial and viralinfections, and upper airway cough syndrome.

As used herein, “urinary incontinence” includes stress incontinence,urge incontinence, total incontinence, and overflow incontinence.

As used herein, “diarrhea” includes acute diarrhea (e.g., acute in onsetand persisting for less than 2 weeks) secondary to viral, bacterial orprotozoal infectious agents, bacterial toxins or drugs, and chronicdiarrhea secondary to medications, osmotic diarrhea, secretoryconditions, inflammatory conditions, malabsorptive conditions, motilitydisorders, chronic infections, and factitious diarrhea.

As used herein, the term “pain” includes: (i) peripheral neuropathicpain, e.g., acute and chronic inflammatory demeyelinatingpolyradiculopathy, alcoholic polyneuropathy, chemotherapy-inducedpolyneuropathy, complex regional pain syndrome (CRPS) Type I and TypeII, entrapment neuropathies (e.g., carpal tunnel syndrome), HIV sensoryneuropathy, iatrogenic neuralgias (e.g., postthoracotomy pain,postmastectomy pain), idiopathic sensory neuropathy, painful diabeticneuropathy, phantom limb pain, postherpetic neuralgia, trigeminalneuralgia, radiculopathy (e.g., cervical thoracic, lumbosacral),sciatica, acute herpes zoster pain, temporomandibular joint disorderpain and postradiation plexopathy; and (ii) central neuropathic pain,e.g., compressive myelopathy from spinal stenosis, HIV myelopathy,multiple sclerosis pain, Parkinson's disease pain, postischemicmyelopathy, post postradiation myelopathy, poststroke pain,posttraumatic spinal cord injury and syringomyelia; and (iii) cancerassociated neuropathic pain, e.g., chemotherapy induced polyneuropathy,neuropathy secondary to tumor infiltration or nerve compression, phantombreast pain, postmastectomy pain, postradiation plexopathy andmyelopathy; (iv) chronic pain, e.g., back pain, rheumatoid arthritis,osteoarthritis, inflammatory pain, non-inflammatory pain, myofascialpain, cancer pain, visceral pain, somatic pain, pelvic pain,musculoskeletal pain, post-traumatic pain, bone pain and idiopathicpain; (v) acute pain, e.g, acute postsurgical pain (includinglaparoscopic, laparatomy, gynecologic, urologic, cardiothoracic,arthroscopic, gastrointestinal, neurologic, orthopedic, oncologic,maxillofacial, ophthalmic, otolaryngologic, soft tissue, plastic,cosmetic, vascular and podiatric surgery, including abdominal surgery,abdominoplasty, adenoidectomy, amputation, angioplasty, appendectomy,arthrodesis, arthroplasty, arthroscopy, bilateral cingulotomy, biopsy,brain surgery, breast biopsy, cauterization, cesarean section,cholecystectomy, circumcision, commissurotomy, cordotomy, cornealtransplantation, cricothoracotomy, discectomy, diverticulectomy,episiotomy, endarterectomy, endoscopic thoracic sympathectomy, foreskinrestoration, fistulotomy, frenectomy, frontalis lift, fundectomy,gastrectomy, grafting, heart transplantation, hemicorporectomy,hemorrhoidectomy, hepatectomy, hernia repair, hypnosurgery,hysterectomy, kidney transplantation, laminectomy, laparoscopy,laparotomy, laryngectomy, lithotripsy, lobotomy, lumpectomy, lungtransplantation, mammectomy, mammoplasty, mastectomy, mastoidectomy,mentoplasty, myotomy, mryingotomy, nephrectomy, nissen fundoplication,oophorectomy, orchidectomy, parathyroidectomy, penectomy, phalloplasty,pneumotomy, pneumonectomy, prostatectomy, psychosurgery, radiosurgery,ritidoplasty, rotationplasty, sigmoidostomy, sphincterotomy,splenectomy, stapedectomy, thoracotomy, thrombectomy, thymectomy,thyroidectomy, tonsillectomy, tracheotomy, tracheostomy, tubal ligation,ulnar collateral ligament reconstruction, ureterosigmoidostomy,vaginectomy, vasectomy, vulvectomy; renal colic; incisional pain;inflammatory incisional pain; nociceptive incisional pain; acuteneuropathic incisional pain following surgery), renal colic, trauma,acute back pain, burn pain, burn dressing change pain, migraine pain,tension headache pain, acute musculoskeletal pain, acute exacerbation orflare of chronic back pain, acute exacerbation or flare ofosteoarthritis, acute exacerbation or flare of chronic pain,breakthrough chronic non-cancer pain, breakthrough cancer pain, acuteexacerbation or flare of rheumatoid arthritis, acute exacerbation orflare of myofacsial pain, acute exacerbation or flare of chronicidiopathic pain, acute exacerbation or flare of neuropathic pain,procedure related pain (e.g., arthroscopy, laparoscopy, endoscopy,intubation, bone marrow biopsy, soft tissue biopsy, catheterization),and other self-limiting pain states.

As used herein, the term “acute pain” refers to self-limiting pain thatsubsides over time and usually lasting less that about 30 days and morepreferably lasting less than about 21 days. Acute pain does not includechronic conditions such as chronic neuropathy, chronic neuropathic painand chronic cancer and non-cancer pain.

As used herein, “neuropathic pain” is pain initiated or caused by aprimary lesion or dysfunction of the nervous system and includes (i)peripheral neuropathic pain and (ii) central neuropathic pain.

As used herein, the term “chronic pain” includes all non-neuropathicpain usually lasting more than 30 days, including inflammatory pain,non-inflammatory pain, muscle pain, joint pain, fascia pain, visceralpain, bone pain and idiopathic pain.

The term “analgesic effectiveness” is defined for purposes of thepresent invention as a satisfactory prevention, reduction in orelimination of pain, along with a tolerable level of side effects, asdetermined by the human patient.

According to the American Academy of Pain Medicine, the American PainSociety and the American Society of Addiction Medicine “addiction” and“addiction disorder” is a primary, chronic, neurobiologic disease, withgenetic, psychosocial, and environmental factors influencing itsdevelopment and manifestations. It is characterized by behaviors thatinclude one or more of the following: impaired control over medicationuse, compulsive use, continued use despite harm, and craving (Sloan andBabul, Expert Opinion on Drug Delivery 2006; 3:489-97). Thepharmaceutical composition of the present invention is in someembodiments intended to treat addiction disorder, particularly opioidaddiction disorder and poly-substance abuse involving opioids. In someembodiments, the dosage form of the invention is intended to reduce oreliminate the craving or desire for opioids and the antisocial,medically harmful and potentially criminal behavior of the patient withthe addiction disorder. The term “therapeutic effectiveness” is definedfor purposes of the present invention as a satisfactory prevention,reduction in or elimination of signs and symptoms of the medicaldisorder, disease or syndrome (e.g., pain, addiction disorder), alongwith a tolerable level of side effects, as determined by the humanpatient.

As used herein, the “Orange Book” as it is commonly known is thedatabase of Approved Drug Products with Therapeutic EquivalenceEvaluations maintained by or on behalf of the US Food and DrugAdministration, (http://www.fda.gov/cder/ob/default.htm, accessed Feb.15, 2008), the content of which is hereby incorporated by reference.

“Drug”, “drug substance”, “substance”, “therapeutic”, “therapeuticagent”, “pharmacological agent”, “pharmaceutical agent”, “active agent”,“active ingredient”, “agent” “active pharmaceutical ingredient” or “API”are used interchangeably and are intended to have their broadestinterpretation as to any therapeutically active substance which isdelivered to a living organism to furnish pharmacological activity orother direct effect in the diagnosis, cure, mitigation, treatment, orprevention of a disease, or to affect the structure or any function ofthe human body. In general, this includes therapeutic agents in all ofthe major therapeutic areas.

As used herein, “dosage forms” is interchangable with “formulations”,“compositions”, “pharmaceutical compositions” or “formulations”. Dosageforms of the invention are modified release dosage forms, which may becontrolled release or delayed release as further defined herein.

The term “subject” for purposes of treatment is used interchangeablywith “patient”, “male”, “female” and “human”, and includes any humansubject or other mammal. A most preferred mammal is a human subject ofany age. It will be obvious to any practitioner of the art that some ofthe embodiments, specifications and claims of the invention are notapplicable to non-human mammals or need to be modified. For example, thedose of invention may vary depending on the species, its weight,metabolism and GI transit time. Similarly, certain behaviors (e.g., drugabuse, drug diversion) and pharmacodynamic effects (e.g., assessment ofmood altering effects or cognitive impairment) are not usually directlyassessed in or applicable to many non-human species. Preferred non-humanmammals are mammals whose medical care is provided by veterinarians,veterinary technicians, paraveterenarians, animal agriculture industrypersonnel, and game and wildlife personnel. Preferred non-human mammalsinclude domesticated farm animals, pets, livestock and wild game.

“Pharmaceutically or therapeutically acceptable excipient or carrier” or“excipient” refers to a substance which does not interfere with theeffectiveness or the biological activity of the active ingredients andwhich is not toxic to the subject. In some embodiments of the presentinvention, pharmaceutically or therapeutically acceptable excipients orcarriers may play a role in imparting or optimizing the rate and extentof absorption or butorphanol or additional drugs in the pharmaceuticalcomposition. In some embodiments of the present invention,pharmaceutically or therapeutically acceptable excipients or carriersmay play a role in stabilizing the butorphanol or additional drugs inthe pharmaceutical composition. Excipients are widely known in the art(see, for example, FDA EAFUS database; FDA Food Additives Status List;FDA GRAS list and database; FDA Color Additive Status List; FDA InactiveIngredients Database; Rowe, Sheskey and Owen, Handbook of PharmaceuticalExcipients, APhA Publications; 5th edition (2006); Goodman & Gilman'sThe Pharmacological Basis of Therapeutics (Brunton, Lazo and Parker,eds, 11th ed., McGraw Hill (2005); Remington: The Science and Practiceof Pharmacy, 21st ed, Lippincott Williams & Wilkins (2005); Martindale:The Complete Drug Reference, 35th Edition, Pharmaceutical Press (2007);United States Pharmacopeia—National Formulary (USP-NF), (USP 30—NF 25,2007), the International Programme on Chemical Safety and HealthCanada's List of Acceptable Non-medicinal Ingredients).

Any pharmaceutically acceptable excipient, including functionalexcipients may be included in the dosage form, in any molecular weight,particle size, viscosity or amount. In some embodiments, the totalamount of pharmaceutically acceptable excipient is about 0.0001% toabout 99.9 percent, preferably about 0.1% to 98 percent and morepreferably about 1% to about 90% on a dry weight basis of thecomposition. In some embodiments, the total amount of individualpharmaceutically acceptable excipient is about 0.001% to about 99percent, preferably about 0.1% to 97 percent and more preferably about1% to about 95% on a dry weight basis of the composition.

In some embodiments, the amount of individual pharmaceuticallyacceptable excipient, including functional excipient in the dosage formis about 0.0001 mg to about 600 mg, more preferably, from about 0.001 mgto about 500 mg, even more preferably from about 0.001 mg to about 400mg, and most preferably from 0.01 mg to about 300 mg.

In certain preferred embodiments of the present invention, an effectiveamount of butorphanol in immediate release form is included in thecontrolled release unit dose butorphanol formulation to be administered.The immediate release form of the butorphanol is preferably included inan amount which is effective to shorten the time to C_(max) of thebutorphanol in the blood (e.g., plasma). One skilled in the art wouldrecognize various means of incorporating the immediate releasebutorphanol into the unit dose. By including such an effective amount ofimmediate release butorphanol in the unit dose, patients may experiencesuperior relief of pain and neuropathy symptoms.

In certain preferred embodiments of the present invention, the dosageform may include, in addition to the butorphanol, substances, process ortechnologies that impart abuse deterrent, abuse resistant or tamperresistant properties to the dosage form, including aversive agents; saiddosage form reducing or preventing opioid abuse, drug abuse, drugmisuse, recreational drug use, drug diversion and toxicity fromintentional or accidental overdose.

As used herein, the term “aversive”, “aversive agents”, “aversionproducing agents” and “aversive compounds” means to compounds containedwithin the dosage form that produce an aversive, undesirable, repugnant,distasteful, unpleasant, unacceptable physiologic effect, unacceptablepsychic effect, or that pharmacologically block or reduce physiologiceffects sought by recreational drug users, addicts and drug abusers,including one or more of the following effects: mood alterations;euphoria, pleasure; a feeling of high; a feeling of drug liking;anxiolysis; sedation; calmness; a state of relaxation; psychotomimesis;hallucinations; alterations in perception, cognition and mental focus;drowsiness; and psychological reinforcement.

In certain preferred embodiments of the present invention, the dosageform may include, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, abuse deterrent or abuse resistant substances,process or technologies known in the art, including one or more aversiveagents. All kinds of aversive agents are contemplated, including,without limitation, antagonists of abusable drugs, laxatives, cutaneousvasodilators, headache producing agents, emetics, emetogenic compound,nausea producing compounds, bittering agents, drugs that cause burningon irritation when in contact with tissue or mucous membranes (e.g.,naso-mucosal irritants, oro-mucosal irritants, respiratory irritants),tissue irritants, gastrointestinal irritants, drugs that precipitatewithdrawal effects, tissue dyes, lakes and colorants, beverage dyes,lakes and colorants, non-tissue staining beverage dyes, lakes andcolorants (i.e., that do not stain or discolor the skin upon ingestion),fecal discolorants, urine discolorants, malodorous agents, opioidantagonists, benzodiazepine antagonists (e.g., flumazenil), cannabinoidantagonists and pharmacologic antagonists to co-abused drugs notcontained in the dosage form. Such aversive agents may be in the dosageform in a releasable, partially releasable or a non-releasable form(i.e., sequestered), the latter being released on tampering the dosageform (e.g., mechanical, thermal, chemical, solvent tampering, ingestionin ways not recommended, and the like). Further, in some embodiments,such aversive agents may be in the dosage form in an amount that doesnot produce an aversive effect or aversion in any, many or substantiallyall patients when taken in accordance with the prescribing informationor the manufacturer's instructions (for example, in small quantities),but which produce an aversive effect when taken in excess (e.g., higherdose or more frequently). In other embodiments, said aversive agentpharmacologically blocks the effects of the butorphanol and/or theeffects of a co-abused drug, said co-abused drug in the same dosage formor in a different dosage form or not an approved or conventionalpharmaceutical product.

The term “tampering” or “tamper” means any manipulation by mechanical,thermal, chemical and/or pharmacologic means which changes the physicalor chemical properties of the dosage form, e.g., to liberate theabusable drugs for immediate release if it is in sustained release form,or to make the abusable drugs available for inappropriate use such asadministration by an alternate route, e.g., parenterally. The tamperingcan be, e.g., by means of crushing, shearing, grinding, mechanicalextraction, solvent extraction, solvent immersion, combustion, heatingor any combination thereof.

The term “abuse”, “drug abuse”, “opioid abuse”, “recreational drug use”and “drug misuse” in the context of the present invention means, use:(i) in quantities or by methods and routes of administration that do notconform to standard medical practice; (ii) outside the scope of specificinstructions for use provided by a qualified medical professional; (iii)outside the supervision of a qualified medical professional; (iv)outside the approved instructions on proper use provided by the drug'slegal manufacturer; (v) which is not in specifically approved dosageforms for medical use as pharmaceutical agents; (vi) where there is anintense desire for and efforts to procure same; (vii) compulsive use;(viii) through acquisition by manipulation of the medical system,including falsification of medical history, symptom intensity, diseaseseverity, patient identity, doctor shopping, prescription forgeries;(ix) where there is impaired control over use; (x) despite harm; (xi) byprocurement from non-medical sources; (xii) by others through sale ordiversion by the individual into the non-medical supply chain; (xiii)for medically unapproved or mood altering purposes.

The term “mood altering” is defined for purposes of the presentinvention to mean that the “high”, “liking”, pleasurable, euphoric,alerting, calming, anxiolytic, auditory and visual perception altering,relaxing, psychotomimetic, rewarding and reinforcing, of the abusabledrug.

The term “abuse resistant”, “abuse deterrent”, “tamper resistant”,“deter abuse” and “resist abuse” (as well of the words “resist” or“deter” when applied to abusable drugs of the invention) are usedinterchangeably in the context of the present invention and includepharmaceutical compositions and methods that resist, deter, discourage,diminish, delay and/or frustrate: (i) the physical, chemical, thermal orpharmacologic manipulation or tampering of the dosage form (e.g.,crushing, shearing, grinding, chewing, dissolving, melting, needleaspiration, inhalation, insufflation, extraction by mechanical, thermaland chemical means, and/or filtration); (ii) use or misuse of the dosageform outside the scope of specific instructions for use provided by aqualified medical professional; (iii) use outside the supervision of aqualified medical professional; (iv) use outside the approvedinstructions on proper use provided by the drug's legal manufacturer(e.g., intravenous use, intranasal use, inhalational use and oralingestion to provide high peak concentrations, use in excess quantities,etc.); (v) the conversion of an extended release dosage form of theinvention into a more immediate release form; (vi) the intentional andiatrogenic increase in physical and psychic effects sought byrecreational drug users, addicts, and patients with pain who have anaddiction disorder; (vii) attempts to procure the dosage form bymanipulation of the medical system and from non-medical sources; (viii)the sale or diversion of the dosage form into the non-medical supplychain and for medically unapproved or unintended mood altering purposes;(ix) the intentional, unintentional or accidental attempts at otherwisechanging the physical, pharmaceutical, pharmacological and/or medicalproperties of the dosage form from what was intended by themanufacturer; (x) the psychic, pleasurable, reinforcing or rewardingeffects of the dosage form when used as directed or when used outsidethe approved instructions on proper use provided by the drug's legalmanufacturer.

All kinds of abuse deterrent agents, excipients, dosage forms andtechnologies are contemplated, including, without limitation, excipientsthat deter or resist extraction of drug with the application ofmechanical, chemical, or thermal energy, use of solvents, use ofsequestered or unsequestered (releasable) antagonists to the drug or toa co-abused drug, use of sequestered or unsequestered (releasable)aversive agents, and use covalently bound moieties that modulate releaseof the butorphanol in vitro, in the GI tract and in the liver.

In some embodiments, one or more aversive agents may be added to theformulation in an amount of less than about 80% by weight, preferablyless than about 60% by weight, more preferably less than about 40% byweight of the dosage form, even more preferably less than about 20% byweight of the dosage form, and most preferably less than about 10 byweight of the dosage form (e.g., 0.000000000000001% to 1%, or0.000000001% to 3%, or 0.0001% to 10%, or 0.001% to 5%, or 1% to 10%, or0.001% to 2%, or 1% or 10%, or 2% to 7%) depending on the particularaversive agent used.

In some embodiments, the aversive agent in the dosage form may be about0.00000000001 mg to about 2000 mg, or about 0.0000001 mg to about 1500mg, or about 0.000001 mg to about 1000 mg, or about 0.0001 mg to about1000 mg, or about 0.001 mg to about 1000 mg, or about 0.01 mg to about1000 mg, or about 0.1 mg to about 1500 mg, or 1 mg to about 800 mg, orabout 1 mg to about 500 mg, or about 1 mg to about 300 mg, or about 1 mgto about 150 mg, or about 5 mg to about 400 mg, or about 5 mg to about200 mg, or about 0.00000000001 mg to about 200 mg, or about0.00000000001 mg to about 100 mg, or about 0.00000000001 mg to about 50mg, or about 0.0000001 mg to about 200 mg, or about 0.0000001 mg toabout 100 mg, or about 0.00001 mg to about 400 mg, or about 0.0001 mg toabout 300 mg.

In some embodiments, the amount of aversive agent in the dosage form ofthe present invention can be a fixed ratio in relation to the amount ofabusable drug in the dosage form. By appropriately selecting thequantity of the aversive agent in the dosage form, aversive effects canbe avoided under conditions of proper medical use (e.g., manufacturersprescribing directions). However, under some conditions of abuse, forexample excessive intake of the dosage form of the invention, thequantity of aversive agent consumed will exceed the “no effect” or“minimum effect” threshold, thereby producing one or more aversiveeffects, for example, e.g., nausea, emesis, diarrhea, laxation,cutaneous vasodilation, headache, bitter taste, naso-mucosal irritation,oro-mucosal irritation, precipitation of abstinence from the abusabledrug of the dosage form, precipitation of abstinence from a co-abuseddrug which is not part of the dosage form, reduction of the pleasurable,mood altering, rewarding, reinforcing, stimulant, depressant or otherpsychic and physiologic effects of the abusable drug or a co-abuseddrug, etc.).

In some embodiments, the “no effect” or “minimum effect” thresholdamount of aversive agent can be exceeded when the dosage form of theinvention is taken in excess of the manufacturer's recommendation by afactor of about 1.5, or about 2, or about 2.5, or about 3, or about 4,or about 5, or about 6, or about 7, or about 8, or about 10, or morethan 10. In some embodiments, the production of an aversive effect canreduce or stop further abuse of the dosage form, thereby reducing theharm or toxicity of the drug in the subject who is tampering, misusingor abusing the dosage form, e.g., addicts, drug abusers and recreationaldrug users.

In some embodiments, the aversive agent in the dosage form may be anopioid antagonist.

Opioid antagonists are well known in the art and include naltrexone,methylnaltrexone, naloxone, nalmefene, cyclazocine, cyclorphan,oxilorphan nalorphine and levallorphan or pharmaceutically acceptablesalt thereof or mixture thereof. In a preferred embodiment, saidantagonist is naltrexone or naloxone. In a most preferred embodiment,said antagonist is naloxone. In some embodiments, the aversive agent inthe dosage form may be an opioid antagonist in the amount of about0.00001 mg to about 800 mg, or about 0.001 mg to about 400 mg, or about0.01 mg to about 200 mg, or about 0.2 mg to about 100 mg, or about 0.2mg to about 50 mg, or 0.2 to 8 mg.

In some embodiments, the ratio of butorphanol base to naloxone base ismore than about: 3:1; 4:1, 5:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1,12:1, 14:1, 16:1, 18:1, 20:1, 22:1, 24:1, 26:1, 28:1, 30:1, 35:1, 40:1,45:1 50:1; 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85:1 or 90:1.

In some embodiments, the ratio of naloxone may be replaced withnaltrexone, and the butorphanol base to naltrexone base ratio is morethan about: 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1, 16:1,18:1, 20:1, 22:1, 24:1, 26:1, 28:1, 30:1; 35:1; 40:1; 45:1 50:1; 55:1,60:1, 65:1, 70:1, 75:1, 80:1, 85:1 or 90:1.

In some embodiments, the present invention is directed to oralpharmaceutical compositions of butorphanol comprising naloxone, wherethe systemic exposure to naloxone as measured by the area under theplasma naloxone concentration-time curve from time 0 to 48 hours or 0 toinfinity (AUC₀₋₄₈ or AUC_(0-inf)) after single dose oral administrationof the untampered or intact dosage form is less than about: 20 ng·hr/mL,18 ng·hr/mL, 15 ng·hr/mL, 12 ng·hr/mL, 10 ng·hr/mL, 8 ng·hr/mL, 7ng·hr/mL, or 6 ng·hr/mL, or 5 ng·hr/mL, 4 ng·hr/mL, or 3 ng·hr/mL, or 2ng·hr/mL, or 1.5 ng·hr/mL, or 1 ng·hr/mL, or 0.8 ng·hr/mL, or 0.7ng·hr/mL, or 0.6 ng·hr/mL, or 0.55 ng·hr/mL, or 0.5 ng·hr/mL, or 0.45ng·hr/mL, or 0.4 ng·hr/mL, 0.35 ng·hr/mL, or 0.3 ng·hr/mL, or 0.25ng·hr/mL, or 0.2 ng·hr/mL. In some embodiments, said AUC is after singledose oral administration of the tampered or crushed dosage form.

In some embodiments, the present invention is directed to oralpharmaceutical compositions of butorphanol comprising naltrexone, wherethe systemic exposure to naltrexone as measured by the area under theplasma naltrexone concentration-time curve from time 0 to 48 hours or 0to infinity (AUC₀₋₄₈ or AUC_(0-inf)) after single dose oraladministration of the untampered or intact dosage form is less thanabout: 20 ng·hr/mL, 18 ng·hr/mL, 15 ng·hr/mL, 12 ng·hr/mL, 10 ng·hr/mL,8 ng·hr/mL, 7 ng·hr/mL, or 6 ng·hr/mL, or 5 ng·hr/mL, 4 ng·hr/mL, or 3ng·hr/mL, or 2 ng·hr/mL, or 1.5 ng·hr/mL, or 1 ng·hr/mL, or 0.8ng·hr/mL, or 0.7 ng·hr/mL, or 0.6 ng·hr/mL, or 0.55 ng·hr/mL, or 0.5ng·hr/mL, or 0.45 ng·hr/mL, or 0.4 ng·hr/mL, 0.35 ng·hr/mL, or 0.3ng·hr/mL, or 0.25 ng·hr/mL, or 0.2 ng·hr/mL. In some embodiments, saidAUC is after single dose oral administration of the tampered or crusheddosage form.

In some embodiments, the present invention is directed to oralpharmaceutical compositions of butorphanol comprising naloxone, wherethe peak plasma naloxone concentration (C_(max)) after single dose oraladministration of the untampered or intact dosage form is less thanabout: 4 ng/mL, 3 ng/mL, 2 ng/mL, 1.5 ng/mL, 1.25 ng/mL, or 1 ng/mL, or0.8 ng/mL, or 0.7 ng/mL, or 0.6 ng/mL, or 0.5 ng/mL, or 0.4 ng/mL, or0.3 ng/mL, or 0.2 ng/mL, or 0.1 ng/mL. In some embodiments, said C_(max)is after single dose oral administration of the tampered or crusheddosage form.

In some embodiments, the present invention is directed to oralpharmaceutical compositions of butorphanol comprising naltrexone, wherethe peak plasma naltrexone concentration (C_(max)) after single doseoral administration of the untampered or intact dosage form is less thanabout: 4 ng/mL, 3 ng/mL, 2 ng/mL, 1.5 ng/mL, 1.25 ng/mL, or 1 ng/mL, or0.8 ng/mL, or 0.7 ng/mL, or 0.6 ng/mL, or 0.5 ng/mL, or 0.4 ng/mL, or0.3 ng/mL, or 0.2 ng/mL, or 0.1 ng/mL. In some embodiments, said C_(max)is after single dose oral administration of the tampered or crusheddosage form.

In some embodiments, the oral butorphanol dosage forms of the inventioncomprising naloxone or naltrexone in the amounts, ratios or exposurelevel in the specifications are abuse deterrent in some, most,substantially all or all recreational opioid users and opioid abuserswhen the dosage form is tampered with and the contents (butorphanol plusnaloxone or butorphanol plus naltrexone) are injected.

In some embodiments, the oral butorphanol dosage forms of the inventioncomprising naloxone or naltrexone in the amounts, ratios or exposurelevel in the specifications are abuse deterrent in some, most,substantially all or all recreational opioid users and opioid abuserswhen the dosage form is tampered with and the contents (butorphanol plusnaloxone or butorphanol plus naltrexone) are taken orally.

In some embodiments, the dosage form comprises butorphanol, optionallymaterial to render said dosage form controlled release and one or moreopioid antagonists, preferably selected from the group comprisingnaloxone, naltrexone and nalmefene; said opioid antagonist having an invitro release rate provided herein. In some embodiments, the butorphanoland the opioid antagonist share the same in vitro release rate(dissolution rate) specifications. In other embodiments, the butorphanoland the opioid antagonist have different in vitro release rate(dissolution rate) specifications referred to herein. In yet otherembodiments, the in vitro release rate (dissolution rate) specificationsreferred to herein are applicable only to the butorphanol.

In some embodiments, the dosage form comprises butorphanol, optionallymaterial to render said dosage form controlled release and one or moreaversive agents; said aversive agent having an in vitro release rateprovided herein. In some embodiments, butorphanol and the aversive agentshare the same in vitro release rate (dissolution rate) specifications.In other embodiments, butorphanol and the aversive agent have differentin vitro release rate (dissolution rate) specifications referred toherein. In yet other embodiments, the in vitro release rate (dissolutionrate) specifications referred to herein are applicable only to thebutorphanol.

It should be noted that the above mentioned aversive agents may, in someembodiments be used in the dosage form of the invention for purposesother than as aversive agents, or for both aversive and non-aversivepurposes. Such non-aversive uses can include, without limitation,pharmaceutical purposes and pharmacologic purposes. For example, in someembodiments, the laxative agent may be used to counteract theconstipating effects of the abusable dosage form of the invention. Insome embodiments, zinc and pharmaceutically acceptable salts of zinc andniacin may be used for pharmaceutical purposes (e.g., pharmaceuticaloptimization, drug release and drug stability).

In some embodiments, an aversive agent incorporated into the oral dosageform shares one, or more dissolution rate specifications, GI deliveryand release specifications and pharmacokinetic parameter specifications(limited to T_(max), HVD and W₅₀) with the oral butorphanol in thedosage form.

In some embodiments, an aversive agent incorporated into the oral dosageform has different dissolution rate specifications, GI delivery andrelease specifications and pharmacokinetic parameter specifications fromthe oral butorphanol in the dosage form.

In one embodiment of the invention, the dosage form includes both animmediate release and extended release component.

In one embodiment of the invention, the dosage form includes a capsulewithin a capsule, each capsule containing a different drug or the samedrug intended for treating the same or a different malady. In somepreferred embodiments, the outer capsule may be an enteric coatedcapsule or a capsule containing an immediate release formulation toprovide rapid plasma concentrations or a rapid onset of effect or aloading dose and the inner capsule contains an extended releaseformulation. In some preferred embodiments, up to 3 capsules within acapsule are contemplated as part of the invention. In one embodiment ofthe invention, the dosage form involves one or more tablets within acapsule, wherein the butorphanol is either in the tablet and/or in oneof the capsules.

In one embodiment of the invention, the formulation is ingested orallyas a tablet or capsule, preferably as a capsule. In another embodimentof the invention, the formulation is administered bucally.

“Therapeutically effective amount” or “therapeutically-effective” refersto the amount of an active agent sufficient to induce a desiredbiological result. That result may be alleviation of the signs,symptoms, or causes of a disease, or any other desired alteration of abiological system.

“Therapeutically effective amount of butorphanol” refers to the amountof oral butorphanol sufficient to prevent, to cure, or at leastpartially arrest a medical disorder, disease, sign or symptom for whichthe butorphanol has been prescribed to a subject.

The term “effective amount” means the quantity of a compound accordingto the invention necessary to prevent, to cure, or at least partiallyarrest a medical disorder, disease, sign or symptom for which thebutorphanol has been prescribed to a subject.

The term “pharmaceutically acceptable salt” as used herein refers to asalt which is toxicologically safe for human and animal administration.Nonlimiting examples of salts include hydrochlorides, hydrobromides,hydroiodides, sulfates, bisulfates, nitrates, citrates, tartrates,bitartrates, phosphates, malates, maleates, napsylates, fumarates,succinates, acetates, terephlhalates, pamoates and pectinates. In someembodiments, the pharmaceutical composition is a salt or complex ofinorganic cation salts, organic salts such primary, secondary, tertiaryand quaternary amines include substituted amines

It is contemplated that the present invention may be used alone or incombination with other drugs to provide additive, complementary, orsynergistic therapeutic effects or for the treatment of entirelydifferent medical conditions.

Other pharmaceutically active ingredients from various therapeuticclasses may also be used in combination with the present invention. Insome embodiment, co-administered may be used to provide additive,complementary, superadditive or synergistic therapeutic effects. In someembodiment, co-administered may be used to provide a differenttherapeutic effects from the present invention or to treat the sideeffects of the present invention. They include, but are not limited todecongestants, analgesics, analgesic adjuvants, antihistamines,expectorants, antitussives, diuretics, anti-inflammatory agents,antipyretics, antirheumatics, antioxidants, laxatives, proton pumpinhibitors, motility modifying agents, vasodilators, inotropes, betablockers, beta adrenergic agonists, drugs to treat asthma and COPD,antiinfectives, antihypertensives, antianginal agents, anticoagulants,lipid and cholesterol lowering drugs, anti-diabetic drugs, hormones,smooth muscle relaxants, skeletal muscle relaxants, bronchodilators,vitamins, trace minerals, amino acids, biological peptides, and drugs totreat disorders, diseases and maladies, and signs and symptoms thereofreferred to in Harrison's Principles of Internal Medicine, 16th Edition,2004, Kasper D L, Braunwald W, Fauci A, Hauser S, Longo D, and Jameson JL (eds)], which is hereby incorporated in its entirety by reference Thedrug being used in combination therapy with the present invention can beadministered by any route, including parenterally, orally, topically,transdermally, sublingually, and the like.

As used herein, “butorphanol responsive conditions”, butorphanolresponsive medical conditions”, “opioid responsive conditions”, “opioidresponsive medical conditions”, “butorphanol or opioid responsivemedical conditions”, “in need to butorphanol”, and the like refer to anymedical condition in which butorphanol can be employed for atherapeutically beneficial outcome.

The terms “medical condition”, “malady”, “disease”, “disorder” and“pathological states” are used interchangeably and are intended to havetheir broadest interpretation to refer to any physiologic, pathologic orpathophysiologic state in a human or other mammal that can be prevented,treated, managed or altered to produce a desired, usually beneficialeffect.

In some embodiments, the oral butorphanol is intended to prevent ortreat pain. A co-administered drug (in the same or different dosageform, by any route of administration) may be used to provide additive,complementary, superadditive or synergistic therapeutic analgesiceffects, including other NSAIDs, NO-NSAIDs, COX-2 selective inhibitors,acetaminophen, tramadol, local anesthetics, antidepressants, betaadrenergic agonists, alpha-2 agonists, selective prostanoid receptorantagonists, cannabinoid agonists, other opioid receptor agonists, NMDAreceptor antagonists, gabapentin, pregabalin, gabapentinoids, neuronalnicotinic receptor agonists, calcium channel antagonists, sodium channelblockers, superoxide dismutase mimetics, p38 MAP kinase inhibitors,TRPV1 agonists, dextromethorphan, dextrorphan, ketamine, glycinereceptor antagonists, antiepileptics, and any other drugs that can beshown by a person proficient in the art to prevent or treat pain.

In other embodiments, particularly preferred combinations includebutorphanol with acetaminophen, NSAID, COX-2 inhibitors, NMDAantagonists, antiepileptics, antidepressants, calcium channel blockers,sodium channel modulators, cannabinoid agonists, muscle relaxants,including cyclobezaprine and drugs selected from the class ofbenzodiazepine agonists, and other opioids agonists

In certain preferred embodiments of the present invention, an effectiveamount of another drug to treat the butorphanol responsive condition, abutorphanol related side effect (e.g., laxative, CNS stimulant oranti-emetic) or a co-existing medical condition may be incorporated intothe dosage form. Such a coadministered drug may be in any form,including immediate release, controlled release and delayed release. Theco-administered drug may be incorporated at a therapeutic dose or asubtherapeutic dose. If included in immediate release form, it may becoated onto the substrates of the present invention. For example, wherethe extended release butorphanol from the formulation is due to acontrolled release coating, the immediate release layer of another drugmay be overcoated on top of the controlled release coating. On the otherhand, the immediate release layer maybe coated onto the surface ofsubstrates wherein the butorphanol is incorporated in a controlledrelease matrix. Where a plurality of the sustained release substratescomprising an effective unit dose of the butorphanol (e.g.,multiparticulate systems including pellets, spheres, beads and the like)are incorporated into a capsule, the immediate release drug may beincorporated into the capsule via inclusion of the sufficient amount ofimmediate release drug as a powder or granulate within the capsule.Alternatively, the capsule itself may be coated with an immediaterelease layer of the drug. One skilled in the art would recognize stillother alternative manners of incorporating the immediate releasebutorphanol into the unit dose. Such alternatives are deemed to beencompassed by the appended claims. By including such an effectiveamount of immediate release drug to treat the same condition as thebutorphanol, it may be possible to reduce the dose of butorphanol in thedosage form.

In certain preferred embodiments of the present invention where thedosage form is delayed onset (e.g, delayed onset, rapid release; delayedonset, extended release; or delayed onset, pulsatile release), aneffective amount of another drug to treat the butorphanol responsivecondition in immediate release form may be particularly advantageous. Incertain preferred embodiments, an NSAID, acetaminophen or a COX-2inhibitor in immediate release form may be advantageously incorporatedinto the dosage form.

In some embodiments, another drug to treat the same condition as theoral butorphanol or to treat a different condition may be incorporatedinto the oral dosage form, where the other drug shares one, or more, orall the dissolution rate specifications, GI delivery and releasespecifications and pharmacokinetic parameter specifications (limited toT_(max), HVD and W₅₀) as the oral butorphanol in the dosage form.

In some embodiments, another drug to treat the same condition as theoral butorphanol or to treat a different condition may be incorporatedinto the oral dosage form, where the other drug has differentdissolution rate specifications, GI delivery and release specificationsand pharmacokinetic parameter specifications from the oral butorphanolin the dosage form, one or more or all said different specificationscontained herein.

In some embodiments, another drug to treat the same condition as theoral butorphanol or to treat a different condition may be incorporatedinto the oral dosage form, where the other drug has differentdissolution rate specifications, GI delivery and release specificationsand pharmacokinetic parameter specifications from the oral butorphanolin the dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

The included drawings are illustrative but not limiting of the methodsand composition of the present invention. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered and obvious to those skilled in the art are within thespirit and scope of the invention.

FIG. 1: Illustrates the gastrointestinal tract of a human subject,including the stomach, the small intestine (duodenum, jejunum andileum), and the colon.

FIG. 2: Provides an expanded view of the anatomy of the colon.

FIG. 3: Illustrates the average pH of various segments of thegastrointestinal tract.

FIG. 4: Illustrates the average pH of for dissolution of many pHsensitive polymers in the various segments of the gastrointestinaltract.

FIG. 5: Illustrates the average gastrointestinal transit times forvarious segments of the gastrointestinal tract.

FIG. 6: Illustrates the in vivo release of a delayed onset, rapidrelease dosage form of oral butorphanol containing an ileo-colonic pHsensitive polymer. The dosage form resists release of the butorphanol atpH less than 5 for a prolonged period of time and releases the contentsof the dosage form at a pH greater than 6.5.

FIG. 7: Illustrates the in vivo release of a delayed onset, rapidrelease dosage form of oral butorphanol containing an ileo-colonic pHsensitive polymer. The dosage form resists release of the butorphanol atpH less than 5.5 for a prolonged period of time and releases thecontents of the dosage form at a pH greater than 7.

FIG. 8: Illustrates the in vivo release of a delayed onset, extendedrelease dosage form of oral butorphanol upon reaching or traversing theileo-cecal junction and transiting into the colon.

FIG. 9: Illustrates the in vivo release of a delayed onset, extendedrelease dosage form of oral butorphanol upon reaching or traversing theileo-cecal junction and transiting into the colon.

FIG. 10: Illustrates a dosage form for colonic release: (1) the outerlayer which dissolves at a pH of about 7; (2) a sustained releasepolymer coating; (3) the butorphanol which has been coated onto anonpareil core or bead (4).

FIG. 11: Illustrates a delayed onset, rapid release dosage form forileo-colonic or colonic release. Following a lag period during which nobutorphanol or very little no butorphanol is released in vivo, thedosage form upon reaching a certain GI environment (e.g., desired pH,pressure, enzymes, microbial flora) or time, or a combination ofvariables, releases the dosage form in a rapid (albeit) pulse or burst.

FIG. 12: Illustrates a delayed onset, extended release dosage form forileo-colonic or colonic release. Following a lag period during which nobutorphanol or very little butorphanol is released in vivo, the dosageform upon reaching a certain GI environment (e.g., desired pH, pressure,enzymes, microbial flora) or time, or a combination of variables,releases the dosage form in an extended release form.

FIG. 13: Time-effect curves depicting antinociceptive effect ofintra-gastric, intra-ileal and intra-colonic butorphanol in the tailflick test. The percent maximum possible effect (% MPE) is plottedversus time. Top curve (intra-colonic, triangle), second from top curve(intra-ileal, large square) and bottom curve (intra-gastric, diamond).

FIG. 14: Time-effect curves depicting antinociceptive effect ofintra-gastric, intra-ileal and intra-colonic butorphanol in the tailflick test. The percent maximum possible effect (% MPE) is plottedversus time. Top curve (intra-colonic, triangle), second from top curve(intra-ileal, large square) and bottom curve (intra-gastric, diamond).

FIG. 15: Time-effect curves depicting the analgesic effect of the orallyadministered butorphanol in the von Frey hair test of mechanicalthreshold of pain in rats with vincristine induced peripheralneuropathy. The mechanical threshold of pain (g) are plotted versustime]

FIG. 16: Time-effect curves depicting the analgesic effect of the orallyadministered butorphanol in the acetone drop test of thermal allodyniaas assessed in rats with vincristine induced peripheral neuropathy. Thepercent maximum possible effect (% MPE) is plotted versus time.

FIG. 17: Time-effect curves depicting the analgesic effect of the orallyadministered butorphanol in the von Frey hair test of mechanicalthreshold of pain in rats with paclitaxel induced peripheral neuropathy.The mechanical threshold of pain (g) are plotted versus time]

FIG. 18: Time-effect curves depicting the analgesic effect of the orallyadministered butorphanol in the acetone drop test of thermal allodyniaas assessed in rats with paclitaxel induced peripheral neuropathy. Thepercent maximum possible effect (% MPE) is plotted versus time.

FIG. 19: Time-effect curves depicting the analgesic effect of the orallyadministered butorphanol in the von Frey hair test of mechanicalthreshold of pain in rats with streptozotocin (STZ) induced diabetesneuropathy. The mechanical threshold of pain (g) are plotted versustime]

FIG. 20: Time-effect curves depicting the analgesic effect of the orallyadministered butorphanol in the acetone drop test of thermal allodyniaas assessed in rats with streptozotocin (STZ) induced diabetesneuropathy. The percent maximum possible effect (% MPE) is plottedversus time.

METHODS OF CARRYING OUT THE INVENTION Dosage Forms

Pharmaceutical composition and methods of the present invention comprisebutorphanol base or pharmaceutically acceptable salts in racemic orenantiomeric form, or mixtures thereof, or prodrugs thereof intendedoral administration as modified release dosage forms.

Preferred modified release dosage forms of the invention include delayedonset formulations (e.g., delayed onset, rapid release; delayed onset,pulsatile release; or delayed onset, extended release) and controlledrelease formulations (also sometimes referred to as prolonged release,slow release, sustained release, extended release, retarded release, andlong acting).

All oral pharmaceutical dosage forms of the invention are contemplated,including oral suspensions, tablets, chewable tablets, capsules,lozenges, effervescent tablets, effervescent powders, powders,solutions, powders for reconstitution, gastroretentive tablets andcapsules, orally disintegrating tablets, oral fast dissolving tablets,oral fast dispersing tablets, oral fast disintegrating dosage forms.

The formulation may optionally comprise excipients, including releasecontrolling excipients and non-release controlling excipient.Non-limiting examples of these auxiliary materials (or pharmaceuticallyacceptable excipients) are (i) Binders such as acacia, alginic acid andsalts thereof, cellulose derivatives, methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, magnesium aluminum silicate,polyethylene glycol, gums, polysaccharide acids, bentonites,hydroxypropyl methylcellulose, gelatin, polyvinylpyrrolidone,polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone,polymethacrylates, hydroxypropylmethylcellulose, hydroxypropylcellulose,starch, pregelatinized starch, ethylcellulose, tragacanth, dextrin,microcrystalline cellulose, sucrose, or glucose, and the like; (ii)Disintegrants such as starches, pregelatinized corn starch,pregelatinized starch, celluloses, cross-linked carboxymethylcellulose,crospovidone, cross-linked polyvinylpyrrolidone, a calcium or a sodiumalginate complex, clays, alginates, gums, or sodium starch glycolate,and any disintegration agents used in tablet preparations; (iii) Fillingagents such as lactose, calcium carbonate, calcium phosphate, dibasiccalcium phosphate, calcium sulfate, microcrystalline cellulose,cellulose powder, dextrose, dextrates, dextran, starches, pregelatinizedstarch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride,polyethylene glycol, and the like; (iv) Stabilizers such as anyantioxidation agents, buffers, or acids, and the like; (v) Lubricantssuch as magnesium stearate, calcium hydroxide, talc, colloidal silicondioxide, sodium stearyl fumarate, hydrogenated vegetable oil, stearicacid, glyceryl behenate, magnesium, calcium and sodium stearates,stearic acid, talc, waxes, Stearowet, boric acid, sodium benzoate,sodium acetate, sodium chloride, DL-leucine, polyethylene glycols,sodium oleate, or sodium lauryl sulfate, and the like; (vi) Wettingagents such as oleic acid, glyceryl monostearate, sorbitan monooleate,sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitanmonooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, orsodium lauryl sulfate, and the like; (vii) Diluents such lactose,starch, mannitol, sorbitol, dextrose, microcrystalline cellulose,dibasic calcium phosphate, sucrose-based diluents, confectioner's sugar,monobasic calcium sulfate monohydrate, calcium sulfate dihydrate,calcium lactate trihydrate, dextrates, inositol, hydrolyzed cerealsolids, amylose, powdered cellulose, calcium carbonate, glycine, orbentonite, and the like; (viii) Anti-adherents or glidants such as talc,corn starch, DL-leucine, sodium lauryl sulfate, and magnesium, calcium,or sodium stearates, and the like; (ix) Pharmaceutically compatiblecarriers such as acacia, gelatin, colloidal silicon dioxide, calciumglycerophosphate, calcium lactate, maltodextrin, glycerin, magnesiumsilicate, sodium caseinate, soy lecithin, sodium chloride, tricalciumphosphate, dipotassium phosphate, sodium stearoyl lactylate,carrageenan, monoglyceride, diglyceride, or pregelatinized starch, andthe like; and (x) excipients referred to herein.

Targeted Gastrointestinal Delivery

Targeted delivery of the butorphanol dosage form of the presentinvention for release and subsequent absorption can be achieved toprovide delayed onset, rapid release dosage forms; delayed onset,pulsatile release dosage forms; delayed onset, extended release dosageforms; and other modified release dosage forms. In addition,conventional extended release products which release the active drugrapidly on ingestion may be coated or embedded with further controlledrelease material designed to provide a lag time before release of drugupon ingestion.

A wide variety of methods for the preparation of delayed onset dosageform are known in the art. These methods may be employed for thepreparation of delayed onset dosage forms of the invention, includingbut not limited to: (i) Prodrug Approach: in some embodiments suchproducts control the rate of release of active drug by azo-bondconjugates, glycoside conjugates, glucuronide conjugates, cyclodextrinconjugates, dextran conjugates, polypeptide conjugates; (ii) PolymericCoating: in some embodiments, such products control the release ofactive drug by coating with pH sensitive polymers and coating withbiodegradable polymers; (iii) Embedding in Matrices: in someembodiments, such products control the release of active drug byembedding in pH sensitive matrices, embedding in biodegradable hydrogelsand matrices (e.g., amylose, chondroitin sulfate, chitosan, inulin,dextran, guar gum, pectin). Other approaches include the use of timedependent systems, Pulsincap®, CODDES® and intestinal pressurecontrolled delivery systems.

In some embodiments, the need for a rapid initial dose may require thata portion of the dose (e.g., up to about 1%, or 3%, or 5%, or 7%, or10%, or 12%, or 15%, or 17%, or 20%, or 22%, or 25%, or 30%) is providedwithout delay as an immediate release dosage form (e.g., withoutlimitation, a capsule within a capsule, a tablet within a capsule, animmediate release overcoat on a tablet or a capsule) in order toachieve, for example, immediate symptom relief

An immediate or controlled release tablet or capsule formulation may beovercoated with one or more polymers to provide butorphanol release inthe appropriate gastrointestinal environment (defined, in someembodiments by location in the GI tract, pH at the point of release,osmotic pressure at the point of release, hydration, microbial flora,and/or the time after ingestion at the point of release).

In some embodiments, the dosage form of the invention is in the form ofa compressed tablet, or a capsule, said tablet or capsule coated with apolymer to retard or delay its release to achieve the objectives of theinvention, said polymers including polymethacrylates (copolymerisate ofmethacrylic acid and either methylmethacrylate or ethyl acrylate(Eudragit®), cellulose based polymers e.g. cellulose acetate phthalate(Aquateric®) or polyvinyl derivatives e.g. polyvinyl acetate phthalate(Coateric®).

In some embodiments, the dosage form of the invention is in the form ofa compressed tablet or a capsule, said tablet or capsule coated with oneor more anionic polymers with methacrylic acid as a functional group(Eudragit™ polymer, Evonik Degussa, Darmstadt, Germany) to retard ordelay its release to achieve the objectives of the invention, saidpolymers including Eudragit™ L 30 D-55 or Eudragit™ L 100-55 whichdissolve in the duodenum or at about pH>5.5, or Eudragit™ L 100 whichdissolves in the jejunum or at a pH of about 6, or Eudragit™ 5100, whichdissolves in the ileum or at a pH o>7.0, or Eudragit™ FS 30D, whichdissolves in the colon or at a pH of about 6, which dissolve at apH>7.0.

In some embodiments, the dosage form of the invention can providedelayed and subsequently ileo-colonic or colonic release over anextended period of time (an extended release) by use of multiplepolymers. In one embodiment, at the center of the dosage form is a corecontaining the butorphanol. The butorphanol is then coated with one ormore layers of polymers that permit the drug to pass through thestomach, duodenum and jejunum (and optionally the ileum) withoutsubstantial absorption. As the dosage form reaches the alkaline pH ofthe ileum and colon (or optionally, upon arrival near or in the colon,for example upon traversing the ileo-cecal junction), the polymer allowspermeability to water and thereby allows drug to diffuse from the dosageform and be available for systemic absorption in the terminal ileumand/or in the colon.

In some embodiments, the dosage form of the invention can providedelayed and subsequently rapid ileo-colonic or colonic release (animmediate pulsed release) by use of materials such as polymers. In thismanner, after a defined lag time, rapid (pulsed) drug release isprovided. For example, a layer composed of drug and organic acid isapplied to the dosage form core. The core is then coated with materialsuch a poly(meth)acrylate with basic groups such as quaternary ammoniumgroups, which become permeable in the presence of water. Duringgastrointestinal transit, water penetrates the coating into the core anddissolves the organic acid. Following the desired lag time, the drug isreleased as an immediate release or pulsed release.

In some embodiments, the dosage form of the invention is in the form ofa capsule, said capsule made from materials known in the art, includinggelatin, plasticizers, starch, hydroxypropylmethyl cellulose (HPMC),pullulan capsule.

In some embodiments of the invention, the butorphanol if formulated asan immediate release or controlled release tablet or capsuleformulation. If used as prepared, the dosage form would usually releasesome of the butorphanol from the dosage form in the stomach, duodenum,jejunum and ileum. Some suitable coatings include U.S. Pat. Nos.4,311,833; 4,377,568; 4,385,078; 4,457,907; 4,462,839; 4,518,433;4,556,552; 4,606,909; 4,615,885; 4,670,287; 5,536,507; 5,567,423;5,591,433; 5,597,564; 5,609,871; 5,614,222; 5,626,875; 5,629,001; and6,608,075, all of which are incorporated herein in their entirety byreference.

In some embodiments of the invention, preferred coating compositionsinclude alkyl and hydroxyalkyl celluloses and their aliphatic esters,e.g., methylcellulose, ethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxybutylcellulose,hydroxyethylethylcellulose, hydroxyprophymethylcellulose,hydroxybutylmethylcellulose, hydroxypropylcellulose phthalate,hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcelluloseacetate succinate; carboxyalkylcelluloses and their salts, e.g.,carboxymethylethylcellulose; cellulose acetate phthalate; celluloseacetate trimellitate, polycarboxymethylene and its salts andderivatives; polyvinyl alcohol and its esters: polyvinyl acetatephthalate; polycarboxymethylene copolymer with sodium formaldehydecarboxylate; acrylic polymers and copolymers, e.g., methacrylicacid-methyl methacrylic acid copolymer and methacrylic acid-methylacrylate copolymer; edible oils such as peanut oil, palm oil, olive oiland hydrogenated vegetable oils; polyvinylpyrrolidone; polyethyleneglycol and its esters: natural products such as shellac, and zein.

In some embodiments of the invention, other preferred coatings includepolyvinylacetate esters, e.g., polyvinyl acetate phthalate;alkyleneglycolether esters of copolymers such as partial ethylene glycolmonomethylether ester of ethylacrylate-maleic anhydride copolymer ordiethyleneglycol monomethylether ester of methylacrylate-maleicanhydride copolymer, N-butylacrylate-maleic anhydride copolymer,isobutylacrylate-maleic anhydride copolymer or ethylacrylate-maleicanhydride copolymer; and polypeptides resistant to degradation in thegastric environment, e.g., polyarginine and polylysine. Other suitablecoatings and methods to make and use delayed onset, rapid release anddelayed onset, extended release, and delayed onset, pulsatile release,and controlled release, and modified release, and extended release, andpulsatile release, and slow release, and duodenal release, and jejunalrelease, and ileal release, and ileo colonic release and colonic releasepharmaceutical compositions and dosage forms of oral butorphanol arewell known to those skilled in the art, including, Colonic Drug Delivery(page 287-294), Wilson C G, In: Modified-Release Drug DeliveryTechnology, Second Edition, Vol. 1, Rathbone M J, Hadgraft J, Roberts MS, Lane M E (eds), Informa Healthcare USA Inc. 2008; Biopolymers andColonic Delivery, Wilson C G, Mukherji G, Shah H K (pages 295-309), In:Modified-Release Drug Delivery Technology, Second Edition, Vol. 1,Rathbone M J, Hadgraft J, Roberts M S, Lane M E (eds), InformaHealthcare USA Inc. 2008; Enteric Coating for Colonic Delivery, Shah HK, Mukherji G, Brogmann B, Wilson C G (pages 311-324), In:Modified-Release Drug Delivery Technology, Second Edition, Vol. 1,Rathbone M J, Hadgraft J, Roberts M S, Lane M E (eds), InformaHealthcare USA Inc. 2008; Programmed Drug Delivery Systems and theColon, Wilson C G, Shah H K, Lee W W, Brogmann B, Mukherji G (pages325-335), In: Modified-Release Drug Delivery Technology, Second Edition,Vol. 1, Rathbone M J, Hadgraft J, Roberts M S, Lane M E (eds), InformaHealthcare USA Inc. 2008; Targeting the Colon Using COLAL™: A NovelBacteria-Sensitive Drug Delivery System, McConnell E L, Basit A W (pages343-348), In: Modified-Release Drug Delivery Technology, Second Edition,Vol. 1, Rathbone M J, Hadgraft J, Roberts M S, Lane M E (eds), InformaHealthcare USA Inc. 2008; Remington: the science of Pharmacy Practice,21^(st) Edition, 2006, Lippincott, Williams & Wilkins, Baltimore, Md.;Pharmaceutical Preformulation and Formulation: A Practical Guide fromCandidate Drug Selection to Commercial Dosage Form. Gibson, M (ed). CRCPress, 2001; Niazi, S. Handbook of Pharmaceutical ManufacturingFormulations Compressed Solid Products (Volume 1 of 6), CRC Press, 2004;Niazi, S. Mollet, H, Grubenmann A, Payne H. Formulation Technology:Emulsions, Suspensions, Solid Forms, Wiley-VCH, 2001; FDA list anddatabase; FDA Color Additive Status List; FDA Inactive IngredientsDatabase; Rowe, Sheskey and Owen, Handbook of Pharmaceutical Excipients,APhA Publications; 5th edition (2006); Rowe, Sheskey and Quinn, Handbookof Pharmaceutical Excipients, 6 edition, Pharmaceutical Press; APhAPublications; 2009; Pharmaceutical Additives Electronic Handbook, ThirdEdition, Michael Ash (compiler), Synapse Information Resources, Inc.; 3Cdr edition (Feb. 19, 2007); and Health Canada's List of AcceptableNon-medicinal Ingredients; Patel et al. Therapeutic Opportunities inColon-Specific Drug-Delivery System, Therapeutic Drug carrier Systems,24(2), 147-202 (2007); Van den Mooter, Colon Drug Delivery, Expert OpinDrug Deliv (2006) 3(1):111-125; Singh. Modified-Release SolidFormulation for Colonic Delivery, Drug Deliv & Formulation 2007, 1,53-56; Kumar et al. Colon Targeted Drug System—An Overview, Current DrugDeliv, 2008, 5, 186-198; Jain et al. Target-Specific Drug Release to theColon, Expert Opin Drug Deliv (2008) 5(5): 483-498; Wei et al. SelectiveDrug Delivery to the Colon Using Pectin-Coated Pellets, PDA J Pharm SciTech Vol. 62, No. 4, 2008; Schellekens et al. Pulsatile Drug Delivery toIleo-Colonic Segments by Structured Incorporation of Disintegrants inpH-Responsive Polymer Coatings, J Controlled Release 132 (2008) 91-98;Coviello et al. Polysaccharide Hydrogels for Modified ReleaseFormulations, J Controlled Release 119 (2007) 5-24; McConnell et al. Anin Vivo Comparison of Intestinal pH & Bacteria as Physiological TriggerMechanisms for Colonic Targeting in Man, J Controlled Release 130 (2008)154-160; Wei et al. Chitosan/Kollicoat SR 30D film-coated pellets ofaminosalicylates for colonic drug delivery J Pharm Sci, 2009 Aug. 4;Yassin et al. New targeted-colon delivery system: in vitro and in vivoevaluation using X-ray imaging. J Drug Target, 2009 Aug. 5; Fan et al.Studies of chitosan/Kollicoat SR 30D film-coated tablets for colonicdrug delivery. Int J Pharm, 2009 Jun. 22; 375(1-2):8-15; Yehia et al.Optimization of budesonide compression-coated tablets for colonicdelivery. AAPS PharmSciTech, 2009; 10(1):147-57; Chandran et al.Microspheres with pH modulated release: Design and characterization offormulation variables for colonic delivery J Microencapsul, 2008 Sep.22:1-11; Gohel et al. Design of a potential colonic drug delivery systemof mesalamine. Pharm Dev Technol 2008; 13(5):447-56; Maestrelli et al.Microspheres for colonic delivery ofketoprofen-hydroxypropyl-beta-cyclodextrin complex. Eur J Pharm Sci 2008May 10; 34(1):1-11; Maestrelli et al. Development of enteric-coatedcalcium pectinate microspheres intended for colonic drug delivery. Eur JPharm Biopharm 2008 June; 69(2):508-18; Fude et al. Preparation and invitro evaluation of pH, time-based and enzyme-degradable pellets forcolonic drug delivery. Drug Dev Ind Pharm 2007 September;33(9):999-1007; Oosegi et al. Novel preparation of enteric-coatedchitosan-prednisolone conjugate microspheres and in vitro evaluation oftheir potential as a colonic delivery system. Eur J Pharm Biopharm, 2008February; 68(2):260-6; Nunthanid et al. Development of time-, pH-, andenzyme-controlled colonic drug delivery using spray-dried chitosanacetate and hydroxypropyl methylcellulose. Eur J Pharm Biopharm, 2008February; 68(2):253-9; Singh Characterization and relevance ofphysicochemical interactions among components of a novelmultiparticulate formulation for colonic delivery. Int J Pharm, 2007Aug. 16; 341(1-2):143-51; Gazzaniga et al. Oral Colon Delivery:Rationale & Time-based Drug Design Strategy. Discov Med, 2006 December;6(36):223-8; Singh Modified-release solid formulations for colonicdelivery. Recent Pat Drug Deliv Formul, 2007; 1(1):53-63; Akhgari et al.Combination of time-dependent & pH-dependent polymethacrylates as asingle coating formulation for colonic delivery of indomethacin pellets.Int J Pharm, 2006 Aug. 31; 320(1-2):137-42; Ibekwe et al. A comparativein vitro assessment of the drug release performance of pH-responsivepolymers for ileo-colonic delivery. Int J Pharm. 2006 Feb. 3;308(1-2):52-60; Al-Saidan et al. In vitro and in vivo evaluation of guargum-based matrix tablets of rofecoxib for colonic drug delivery. CurrDrug Deliv, 2005 April; 2(2):155-63; Basit. Advances in colonic drugdelivery. Drugs. 2005; 65(14):1991-2007; Bott et al. In vivo evaluationof a novel pH- & time-based multiunit colonic drug delivery system.Aliment Pharmacol Ther. 2004 Aug. 1; 20(3):347-53; Qi et al. A novel pH-and time-dependent system for colonic drug delivery. Drug Dev Ind Pharm.2003 July; 29(6):661-7; 21: Shareef et al. Colonic drug delivery: anupdated review. AAPS PharmSci. 2003; 5(2):E17. Review. PubMed PMID:12866944; Tuleu et al. Colonic delivery of sodium butyrate via oralroute: acrylic coating design of pellets and in vivo evaluation in rats.Methods Find Exp Clin Pharmacol. 2001 June; 23(5):245-53; Gupta et al. Anovel pH- & time-based multi-unit potential colonic drug deliverysystem. II. Optimization of multiple response variables. Int J Pharm.2001 Feb. 1; 213(1-2):93-102; Gupta et al. A novel pH- and time-basedmulti-unit potential colonic drug delivery system. I. Development. Int JPharm. 2001 Feb. 1; 213(1-2):83-91; Muraoka et al. Evaluation ofintestinal pressure-controlled colon delivery capsule containingcaffeine as a model drug in human volunteers. J Control Release. 1998Mar. 2; 52(1-2):119-29; Niwa et al. Preparation & evaluation of atime-controlled release capsule made of ethylcellulose for colondelivery of drugs. J Drug Target. 1995; 3(2):83-9. Erratum in: J DrugTarget 96; 3(6):478; Ashford et al. Targeting drugs to the colon:delivery systems oral administration. J Drug Target. 1994; 2(3):241-57,all hereby incorporated by reference in their entirety.

In some embodiments of the invention, the coating material may be mixedwith various excipients including plasticizers such as triethyl citrate,acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutylsubacute, dibutyl tartrate, dibutyl maleate, dibutyl succinate anddiethyl succinate and inert fillers such as chalk or pigments.

The composition and thickness of the coating may be selected to dissolveimmediately upon contact with the digestive juice of the intestine.Alternatively, the composition and thickness of the external coating maybe selected to be a time-release coating which dissolves over a selectedperiod of time, as is well known in the art.

The amount of enteric coating depends on the particular coatingcomposition used and is preferably sufficient to substantially preventthe absorption of in the stomach, duodenum, jejunum and, in someembodiments, the ileum as well.

In some embodiments of the invention, hydroxyalkyl celluloses and theiraliphatic esters, carboxyalkyl celluloses and their salts,polycarboxymethylene and its salts and derivatives, polyvinyl alcoholand its esters, polycarboxymethylene copolymer with sodium formaldehydecarboxylates, polyvinylpyrrolidone, and polyethylene glycol and itsesters can be applied as coatings by first dissolving the compound in aminimum amount of water. Alcohol is then added to the point of incipientcloudiness. The mixture can then be applied by conventional techniques.

In some embodiments, application of cellulose acetate phthalate may beaccomplished by simply dissolving the cellulose acetate phthalate in aminimum amount of alcohol and then applying by conventional techniques.Hydrogenated vegetable oils may be applied by first dissolving the oilin a minimal amount of a non-polymer solvent, such as methylenechloride, chloroform or carbon tetrachloride, then adding alcohol to thepoint of incipient cloudiness and then applying by conventionaltechniques.

In some embodiments, the dosage form of is a capsule or tablet, saiddosage form pre-coated with an excipient, prior to coating with apolymer.

In some embodiments, the capsule dosage form is sealed after filling inthe overlapping region of capsule body and cap by commonly known sealingtechniques like banding or applying a sealing liquid and/or heat to thegap between capsule body and cap. Preferred is a sealing process, inwhich a sealing liquid which may include a solvent applied individuallyand uniformly to the external edge of the gap of a capsule to be sealedto form a liquid ring around the circumference of the capsule, removingexcess sealing liquid from the exterior of the capsule and drying thecapsule by applying thermal energy from outside. Such a sealing beforecoating can prevent problems e.g. with non-uniformity of the coating atthe gap or development of fissures during storage under stressingconditions, which can lead to early leaking of the capsule content intothe stomach. In some embodiments, the banding is achieved through theapplication of a ring of liquid gelatin or hypromellose on the externalsurface of the capsule. In some embodiments, a double-band sealingtechnique is used to ensure ensures that if an air bubble or unevennessoccurs in the first band, it will be eliminated by the secondapplication. Capsule banding can provide tamper evidence, detercounterfeiting, improve mechanical strength, provide color branddifferentiation, improve product stability and reduce oxygen diffusion.

For rapid release of the drug from the dosage form in some embodiments,the composition of the coating will usually provide substantial orcomplete disintegration of the coating in the preferred anatomiclocation and/or at the preferred time after oral ingestion and/or in thepreferred gastrointestinal environment, including preferred pH,preferred osmotic pressure in the lumen, preferred osmotic pressure inthe dosage form, preferred hydration level, preferred microbialenvironment, preferred level of GI peristalsis or agitation.

For controlled or slow release of the drug from the dosage form in someembodiments, the composition of the pH sensitive coating will dissolve,but other controlled release mechanisms will provide for slow release ofthe drug in the preferred anatomic location and/or at the preferred timeafter oral ingestion and/or in the preferred gastrointestinalenvironment, including preferred pH, preferred osmotic pressure in thelumen, preferred osmotic pressure in the dosage form, preferredhydration level, preferred microbial environment, preferred level of GIperistalsis or agitation.

In some embodiments, for rapid release in the small intestine anycoating can be used which ensures that the dosage form does notdisintegrate until it is emptied from the stomach. The coating may beone which is pH sensitive and which completely dissolves in the smallintestine. Typical coating thicknesses will be in the range 2 to 30 mgpolymer per cm² of capsule surface, preferably 5 to 15 mg polymer percm² of capsule surface, but this will vary greatly depending on thechoice of coating. For a capsule of size 1 with a surface area ofapproximately 4 cm² this represents a weight gain of 20 mg to 60 mg percapsule (50 to 150 μm).

In some embodiments, preferred coating materials are those whichdissolve at a pH between 5 and 7.6, for example, >about 5, or >about5.2, or >about 5.5, or >about 5.7, or >about 6, or >about 6.1, or >about6.2, or >about 6.3, or >about 6.4, or >about 6.5, or >about 6.6,or >about 6.7, or >about 6.8, or >about 6.9, or >about 7, or >about 7.2,or >about 7.4, or >about 7.6.

In some embodiments, preferred coating materials include polymers suchas cellulose acetate trimellitiate (CAT), hydroxypropylmethyl cellulosephthalate (HPMCP), polyvinyl acetate phthalate (PVAP), cellulose acetatephthalate (CAP) and shellac. In some embodiments, especially preferredmaterials for aqueous film coating are copolymers of methacrylic acidand ethyl acrylate, Eudragit® L30D-55 (Evonik Degussa, Darmstadt,Germany).

In some embodiments, for release in the terminal ileum or colon anycoating can be used which ensures that the dosage form does notdisintegrate until it is reaches the desired location. In someembodiments, the coating may be one which is pH-sensitive,redox-sensitive or sensitive to particular enzymes or bacteria, suchthat the coating only dissolves or finishes dissolving in the colon.Thus the capsules will not release the drug until it is in the terminalileum or colon.

In some embodiments, preferred coating materials are those whichdissolve at a pH of 7 or above. Generally, such coatings only start todissolve when they have left the stomach and passed through the duodenumand in cases the jejunum and/or terminal ileum. Generally, by the timethe dosage form has reached the terminal ileum or colon the coating willhave completely dissolved. Such a coating can be made from a variety ofpolymers including, without limitation, cellulose acetate trimellitiate(CAT) hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinyl acetatephthalate (PVAP), cellulose acetate phthalate (CAP), shellac andcopolymers of methacrylic acid and ethyl acrylate. In some embodiments,especially preferred materials for aqueous film coating are copolymersof methacrylic acid and ethyl acrylate to which a monomer ofmethylacrylate has been added during polymerization. (Eudragit™ FS 30 D,Evonik Degussa, Darmstadt, Germany). Due to the free carboxylic acidgroup the polymer dissolves at pH 7 or above making it particularlysuitable for delivery into the colon.

It should be noted that when delayed but (subsequently) sustainedrelease of butorphanol is desired, upon dissolution or disintegration ofthe pH sensitive coating or material, a variety of mechanisms canprovide extended release of the drug, including diffusion from matrix,membranes or pores, osmotic pressure, hydration, etc)

Using preparation Eudragit™ FS 30D a coating thickness of 5 to 15 mgpolymer per cm² of capsule surface is preferred in some embodiments.

The colonic region is rich in microbial anaerobic organisms providingreducing conditions. Thus the coating may suitably comprise a materialwhich is redox-sensitive. Such coatings may comprise azopolymers whichcan for example consist of a random copolymer of styrene andhydroxyethyl methacrylate, cross-linked with divinylazobenzenesynthesized by free radical polymerization, the azopolymer being brokendown enzymatically and specifically in the colon or may consist ofdisulphide polymers.

Other materials providing release in the colon are amylose, for examplea coating composition can be prepared by mixing amylose-butan-1-olcomplex (glassy amylose) with an aqueous dispersion of Ethocel or acoating formulation comprising an inner coating of glassy amylose and anouter coating of cellulose or acrylic polymer material, calciumpectinate, pectin, a polysaccharide which is totally degraded by colonicbacterial enzymes, chondroitin sulfate and resistant starches, dextranhydrogels, modified guar gum such as borax modified guar gum,cyclodextrins, beta.-cyclodextrin, saccharide containing polymers, whichcan include a polymeric construct comprising a syntheticoligosaccharides-containing biopolymer including methacrylic polymerscovalently couples to oligosaccharides such as cellobiose, lactalose,raffinose, and stachyose, or saccharide-containing natural polymersincluding modified mucopolysaccharides such as cross-linked chondroitinsulfate and metal pectin salts, for example calcium pectate,methacrylate-galactomannan and pH sensitive hydrogels.

Pharmaceutical compositions of the present invention can be preparedusing methods described in the art. There is a wide body of literatureand other prior art on the delivery, release and absorption of drug fromoral dosage forms wherein said delivery, release and absorption is“targeted”, i.e., where said delivery, release and absorption is: (i)achieved at the desired anatomic location of the GI tract; (ii)substantially avoided at certain anatomic locations of the GI tract;(iii) achieved after a particular amount of time has elapsedpost-ingestion; (iv) achieved when the GI environment meets certainconditions (e.g., pH, electrolyte concentration, enzymes, hydration,bacterial flora, and the like).

Pharmaceutical compositions of the present invention can be preparedusing methods described, referenced or disclosed in U.S. Pat. Nos.7,196,059, 7,189,414, 7,163,696, 7,157,444, 7,119,079, 7,112,578,7,109,239, 7,094,425, 7,041,651, 7,030,082, 7,022,683, 6,930,093,6,919,348, 6,916,791, 6,897,205, 6,893,662, 6,867,183, 6,852,693,6,824,790, 6,777,000, 6,770,625, 6,761,901, 6,747,014, 6,743,445,6,734,170, 6,727,287, 6,699,848, 6,692,766, 6,677,321, 6,669,951,6,632,454, 6,632,451, 6,630,453, 6,555,136, 6,552,072, 6,531,152,6,525,078, 6,432,967, 6,428,968, 6,346,547, 6,340,476, 6,326,364,6,277,411, 6,238,689, 6,231,888, 6,228,396, 6,217,904, 6,200,605,6,200,602, 6,197,763, 6,166,044, 6,166,024, 6,106,864, 6,074,689,6,063,402, 6,039,975, 5,948,407, 5,914,132, 5,905,081, 5,889,028,5,866,619, 5,849,327, 5,846,983, 5,843,479, 5,840,332, 5,814,336,5,811,388, 5,744,166, 5,691,343, 5,686,106, 5,686,105, 5,681,584,5,672,359, 5,670,158, 5,656,294, 5,656,290, 5,651,983, 5,631,022,5,554,388, 5,525,634, 5,514,663, 5,482,718, 5,183,802, 5,122,376,4,904,474, 4,705,515 and 4,627,851, and in US Patent Application No.20070167416, 20070112075, 20070087939, 20070072828, 20070071820,20070071806, 20070060580, 20070059366, 20070054945, 20070026067,20070020254, 20070020197, 20070003626, 20060280795, 20060251720,20060223787, 20060189635, 20060177507, 20060121091, 20060105045,20060099243, 20060083718, 20060045865, 20060041109, 20060003995,20050287276, 20050281781, 20050260262, 20050249716, 20050222040,20050220861, 20050209271, 20050208132, 20050186267, 20050182134,20050181053, 20050169996, 20050158408, 20050153908, 20050153907,20050152978, 20050118326, 20050112201, 20050107334, 20050101611,20050090473, 20050090451, 20050069550, 20050058701, 20050043298,20050009848, 20050009768, 20050009767, 20050009766, 20050008702,20050008688, 20040267240, 20040258754, 20040253304, 20040241173,20040229831, 20040224898, 20040219216, 20040186045, 20040185107,20040176319, 20040162263, 20040162259, 20040161459, 20040147445,20040142880, 20040126422, 20040121967, 20040110837, 20040109894,20040062778, 20040052846, 20040038866, 20040017387, 20040013687,20030207851, 20030194439, 20030181380, 20030170181, 20030162717,20030152617, 20030133978, 20030083232, 20030077326, 20030069170,20030040497, 20030022843, 20030008914, 20020147156, 20020127198,20020110593, 20020110590, 20020098235, 20020058061, 20020035139,20020015729, 20010052137, 20010039262, 20010036473, 20010031748 and20010026807.

Pharmaceutical compositions of the present invention can be prepared toprovide targeted delivery of butorphanol, wherein the targeted deliveryof the immediate or controlled release dosage forms can advantageouslyprovide, among other things, (i) improved efficacy; (ii) improvedsafety; (iii) reduced appeal to drug addicts, drug abusers andrecreational drug users; (iv) reduced nausea; (v) reduced drowsiness;(vi) reduced psychic effects desired by drug addicts, drug abusers andrecreational drug users; (vii) reduced desirability for co-abuse withalcohol or other drugs of abuse; and (viii) reduced risk of diversion.

Pharmaceutical compositions of the present invention can be preparedusing methods described in the art achieve delivery, release andabsorption of drug from oral dosage forms, wherein said delivery,release and absorption is “targeted”, e.g., by way of non-limitingexamples, where said delivery, release and absorption is: (i) achievedat the desired anatomic location of the GI tract (e.g., upon arrival inthe duodenum, or jejum, or ileum, or ileo-cecal junction, or cecum, orascending colon, or transverse colon, or descending colon); (ii)substantially avoided at certain anatomic locations of the GI tract(e.g., stomach, or stomach and duodenum, or stomach, duodenum andjejunum, or stomach, duodenum, jejunum and ileum); (iii) achieved aftera particular amount of time has elapsed post-ingestion (e.g., ≧1.5 hoursor ≧2 hours, or ≧2.5 hours, or ≧3 hours, or ≧3.5 hours, or ≧4 hours, or≧4.5 hours, or ≧5 hours, or ≧5.5 hours, or ≧6 hours, or ≧6.5 hours, or≧7 hours, or ≧7.5 hours); (iv) achieved when the dosage form has come incontact or substantial contact or sustained contact with a desiredgastrointestinal pH environment (e.g., pH>3, or pH>3.5, or pH>4, orpH>4.5, or pH, >5, or pH>5.5, or pH>6, or pH>7, or pH>7.5, or pH>7.8);(v) achieved when the dosage form has come in contact with desiredmicrobial flora (e.g., colonic microbial flora); (vi) achieved when theGI environment meets certain other conditions (e.g., electrolyteconcentration, enzymes, hydration, and the like); (vii) a combination oftwo or more of the foregoing.

Pharmaceutical compositions of the present invention can be preparedusing methods described, referenced or disclosed in U.S. Pat. Nos.7,196,059, 7,189,414, 7,163,696, 7,157,444, 7,119,079, 7,112,578,7,109,239, 7,094,425, 7,041,651, 7,030,082, 7,022,683, 6,930,093,6,919,348, 6,916,791, 6,897,205, 6,893,662, 6,867,183, 6,852,693,6,824,790, 6,777,000, 6,770,625, 6,761,901, 6,747,014, 6,743,445,6,734,170, 6,727,287, 6,699,848, 6,692,766, 6,677,321, 6,669,951,6,632,454, 6,632,451, 6,630,453, 6,555,136, 6,552,072, 6,531,152,6,525,078, 6,432,967, 6,428,968, 6,346,547, 6,340,476, 6,326,364,6,277,411, 6,238,689, 6,231,888, 6,228,396, 6,217,904, 6,200,605,6,200,602, 6,197,763, 6,166,044, 6,166,024, 6,106,864, 6,074,689,6,063,402, 6,039,975, 5,948,407, 5,914,132, 5,905,081, 5,889,028,5,866,619, 5,849,327, 5,846,983, 5,843,479, 5,840,332, 5,814,336,5,811,388, 5,744,166, 5,691,343, 5,686,106, 5,686,105, 5,681,584,5,672,359, 5,670,158, 5,656,294, 5,656,290, 5,651,983, 5,631,022,5,554,388, 5,525,634, 5,514,663, 5,482,718, 5,183,802, 5,122,376,4,904,474, 4,705,515 and 4,627,851, and in US Patent Application No.20070167416, 20070112075, 20070087939, 20070072828, 20070071820,20070071806, 20070060580, 20070059366, 20070054945, 20070026067,20070020254, 20070020197, 20070003626, 20060280795, 20060251720,20060223787, 20060189635, 20060177507, 20060121091, 20060105045,20060099243, 20060083718, 20060045865, 20060041109, 20060003995,20050287276, 20050281781, 20050260262, 20050249716, 20050222040,20050220861, 20050209271, 20050208132, 20050186267, 20050182134,20050181053, 20050169996, 20050158408, 20050153908, 20050153907,20050152978, 20050118326, 20050112201, 20050107334, 20050101611,20050090473, 20050090451, 20050069550, 20050058701, 20050043298,20050009848, 20050009768, 20050009767, 20050009766, 20050008702,20050008688, 20040267240, 20040258754, 20040253304, 20040241173,20040229831, 20040224898, 20040219216, 20040186045, 20040185107,20040176319, 20040162263, 20040162259, 20040161459, 20040147445,20040142880, 20040126422, 20040121967, 20040110837, 20040109894,20040062778, 20040052846, 20040038866, 20040017387, 20040013687,20030207851, 20030194439, 20030181380, 20030170181, 20030162717,20030152617, 20030133978, 20030083232, 20030077326, 20030069170,20030040497, 20030022843, 20030008914, 20020147156, 20020127198,20020110593, 20020110590, 20020098235, 20020058061, 20020035139,20020015729, 20010052137, 20010039262, 20010036473, 20010031748 and20010026807, which are hereby fully incorporated by reference herein intheir entirety.

Pharmaceutical compositions of the present invention can be preparedusing methods described, referenced or disclosed in Singh and Kim, Int JPharm. 2007; 341:143-51; Jain et al., Crit Rev Ther Drug Carrier Syst.2006; 23:349-400; Ugurlu et al., Eur J Pharm Biopharm. 2007; 67:202-10;Sinha et al., J Pharm Pharmacol. 2007; 59:359-65; Gazzaniga et al.,Discov Med. 2006; 6:223-8; Rhaman et al., AAPS PharmSciTech. 2006;7:E47; Akhgari et al., Int J Pharm. 2006; 320:137-42; Bourgeois et al.,J Drug Target. 2005; 13:277-84; Curini et al., Bioorg Med Chem Lett.2005; 15:5049-52; Lamprecht et al., J Control Release. 2005; 104:337-46;Verbeke et al., Aliment Pharmacol Ther. 2005; 21:187-94; Bruce et al.,Eur J Pharm Biopharm. 2005; 59:85-97; Lamprecht et al., Eur J PharmBiopharm. 2004; 58:37-43; Mura et al., J Drug Target. 2003; 11:365-71;Lamprecht et al., J Control Release. 2003; 90:313-22; Wiwattanapatapeeet al., J Control Release. 2003; 88:1-9; Waterman et al., J ControlRelease. 2003; 86:293-304; Park et al., Arch Pharm Res. 2002; 25:964-8;Tuleu et al., Aliment Pharmacol Ther. 2002; 16:1771-9; Gupta et al.,Drug Dev Ind Pharm. 2002; 28:207-15; Turkoglu et al., Eur J PharmBiopharm. 2002; 53:65-73; Tuleu et al., Methods Find Exp Clin Pharmacol.2001; 23:245-53; Stubbe et al., J Control Release. 2001; 75:103-14;Shibata et al., J Pharm Pharmacol. 2001; 53:441-7; Jeong et al., JControl Release. 2001; 71:175-82; Hu et al., J Pharm Pharmacol. 2000;52:1187-93; Hu et al., Pharm Res. 2000; 17:160-7; Ahrabi et al., Eur JPharm Sci. 2000; 10:43-52; Yoshikawa et al., J Pharm Pharmacol. 1999;51:979-89; Ahrabi et al., Drug Dev Ind Pharm. 1999; 25:453-62; Hu etal., J Control Release. 1998; 56:293-302; Kakoulides et al., J ControlRelease. 1998; 52:291-300; Kakoulides et al., J Control Release. 1998;54:95-109; Muraoka et al., J Control Release. 1998; 52:119-29; Takaya etal., J Control Release. 1998; 50:111-22; Muraoka et al., Nippon Rinsho.1998; 56:788-94; Kenyon et al, Aliment Pharmacol Ther. 1997; 11:205-13;Takaya et al., J Drug Target. 1997; 4:271-6; Matsuda et al., J DrugTarget. 1996; 4:59-67; Jones S P, J Drug Target. 1996; 3:477-8; Fedoraket al., Gastroenterology. 1995; 108:1688-99; Takaya et al., J PharmPharmacol. 1995; 47:474-8; Niwa et al., J Drug Target. 1995; 3:83-9;Ashford and Fell, J Drug Target. 1994; 2:241-57, Colonic Drug Delivery(page 287-294), Wilson C G, In: Modified-Release Drug DeliveryTechnology, Second Edition, Vol. 1, Rathbone M J, Hadgraft J, Roberts MS, Lane M E (eds), Informa Healthcare USA Inc. 2008; Biopolymers andColonic Delivery, Wilson C G, Mukherji G, Shah H K (pages 295-309), In:Modified-Release Drug Delivery Technology, Second Edition, Vol. 1,Rathbone M J, Hadgraft J, Roberts M S, Lane M E (eds), InformaHealthcare USA Inc. 2008; Enteric Coating for Colonic Delivery, Shah HK, Mukherji G, Brogmann B, Wilson C G (pages 311-324), In:Modified-Release Drug Delivery Technology, Second Edition, Vol. 1,Rathbone M J, Hadgraft J, Roberts M S, Lane M E (eds), InformaHealthcare USA Inc. 2008; Programmed Drug Delivery Systems and theColon, Wilson C G, Shah H K, Lee W W, Brogmann B, Mukherji G (pages325-335), In: Modified-Release Drug Delivery Technology, Second Edition,Vol. 1, Rathbone M J, Hadgraft J, Roberts M S, Lane M E (eds), InformaHealthcare USA Inc. 2008; Targeting the Colon Using COLAL™: A NovelBacteria-Sensitive Drug Delivery System, McConnell E L, Basit A W (pages343-348), In: Modified-Release Drug Delivery Technology, Second Edition,Vol. 1, Rathbone M J, Hadgraft J, Roberts M S, Lane M E (eds), InformaHealthcare USA Inc. 2008, Niazi, S. Handbook of PharmaceuticalManufacturing Formulations: Compressed Solid Products (Volume 1 of 6),CRC Press, 2004, which are hereby fully incorporated by reference hereinin their entirety.

Controlled-Release Dosage Forms

All oral extended release pharmaceutical dosage forms of the inventionare contemplated. The preparation of oral extended releasepharmaceutical dosage forms has been described in the art—see—^(se)e forexample, (i) Remington: the science of Pharmacy Practice, 21^(st)Edition, 2006, Lippincott, Williams & Wilkins, Baltimore, Md.; and (ii)Pharmaceutical Preformulation and Formulation: A Practical Guide fromCandidate Drug Selection to Commercial Dosage Form. Gibson, M (ed). CRCPress, 2001; and (iii) Niazi, S. Handbook of PharmaceuticalManufacturing Formulations: Compressed Solid Products (Volume 1 of 6),CRC Press, 2004 (iiib) Niazi, S. Handbook of PharmaceuticalManufacturing Formulations: Uncompressed Solid Products (Volume 2 of 6),CRC Press, 2004; and (iv) Mollet, H, Grubenmann A, Payne H. FormulationTechnology: Emulsions, Suspensions, Solid Forms, Wiley-VCH, 2001; (v)Donald Wise, Handbook of Pharmaceutical Controlled Release Technology,CRC; 1st edition (Aug. 15, 2000); (vi) Chemg-ju Kim, Controlled ReleaseDosage Form Design, Informa Healthcare (Oct. 25, 1999); (vii) XiaolingLi, Design of Controlled Release Drug Delivery Systems, McGraw-HillProfessional; 1 edition (Nov. 3, 2005); (viii) Jean-Maurice Vergnaud,Controlled Drug Release Of Oral Dosage Forms, CRC (Jul. 31, 1993); (ix)L. T. Fan and S. K. Singh. Controlled Release: A Quantitative Treatment,Springer-Verlag (July 1989); (x) Tapash K. Ghosh and Bhaskara R. Jasti(eds). Theory and Practice of Contemporary Pharmaceutics, CRC; 2Rev Ededition (Nov. 23, 2004); (xi) Xiaoling Li and Bhaskara R. Jasti (eds).Design of Controlled release Drug Delivery Systems; (xii) Anya M.Hillery, Andrew W. Lloyd and James Swarbrick (eds). Drug Delivery andTargeting: For Pharmacists and Pharmaceutical Scientists, CRC (Sep. 27,2001); (xiii) Ram I. Mahato. Pharmaceutical Dosage Forms and DrugDelivery, CRC; 1 edition (Jun. 7, 2007); (xiv) Vasant V. Ranade andMannfred A. Hollinger. Drug Delivery Systems, Second Edition, CRC; 2edition (Aug. 26, 2003); (xv) Ashok Katdare and Mahesh Chaubal (eds).Excipient Development for Pharmaceutical, Biotechnology, and DrugDelivery Systems, Informa Healthcare; 1 edition (Jul. 28, 2006); and(xvi) Binghe Wang, Teruna J. Siahaan and Richard A. Soltero. DrugDelivery: Principles and Applications, Wiley-Interscience (Mar. 28,2005), all of which are hereby incorporated in their entirety byreference.

A wide variety of methods for the preparation of controlled releasedosage form are known in the art. These methods may be employed for thepreparation of controlled release dosage forms of the invention,including but not limited to: (i) Diffusion-controlled Products: in someembodiments such products employ a water-insoluble polymer to controlthe flow of water and the subsequent egress of dissolved drug from thedosage form. Both diffusion and dissolution processes are involved. In“reservoir” systems, a core of drug is coated with the polymer and, in“matrix” systems, the drug is dispensed throughout the matrix. Cellulosederivatives are commonly used in the reservoir systems, while the matrixsystems may use methylacrylate-methyl methacrylate, polyvinyl chloride,hydrophilic polymers such as cellulose derivatives or fatty compoundsincluding carnauba wax; (ii) Dissolution-Controlled Products: in someembodiments such products control the rate of dissolution of the drug(and therefore absorption) by slowly soluble polymers or bymicroencapsulation. Once the coating is dissolved, the active drugbecomes available for dissolution. By varying the thicknesses or amountof coating and its composition, the rate of active drug release can becontrolled. Some dosage forms contain a portion of the total dose as inimmediate release form to provide an early “pulse dose”. Spheroid(pellet) dosage forms of diffusion or dissolution-controlled productscan be encapsulated or prepared as a tablet. One potential advantage ofencapsulated spheroid products is that the onset of absorption is lesssensitive to gastric emptying, since the entry of the spheroids into theduodenum tends to be more uniform than with non-disintegratingextended-release tablet formulations; (iii) Erosion Products: in someembodiments, such products control the release of active drug by theerosion rate of a carrier matrix. The release rate is determined by therate of erosion; (iv) Osmotic Pump Systems: in some embodiments suchproducts control the rate of release of active drug by the constantinflow of water across a semipermeable membrane into a reservoir whichcontains an osmotic agent. The drug is either mixed with the agent or islocated in a reservoir. The dosage form contains one or more smallpassageways, or through pores within a membrane through which drug insuspension or solution is pumped at a rate determined by the rate ofentry of water due through osmotic pressure. The rate of release is canbe kept relatively constant; (v) Ion Exchange Resins: in someembodiments, such products control the release of active drug bound toan ion exchange resin by release of drug in the ionic environment withinthe GI tract.

The preparation of oral extended release pharmaceutical dosage forms hasalso been described in the art. Nonlimiting examples are provided inU.S. Pat. Nos. 7,427,414; 7,422,758; 7,413,750; 7,413,749; 7,387,793;7,316,821; 7,229,642; 7,198,803; 7,189,414; 7,125,567; 7,074,430;7,070,806; 7,052,706; 6,979,463; 6,936,275; 6,932,981; 6,905,709;6,902,742; 6,793,936; 6,733,783; 6,730,325; 6,726,931; 6,716,449;6,709,677; 6,699,508; 6,699,506; 6,692,769; 6,692,766; 6,682,759;6,667,060; 6,645,527; 6,599,529; 6,579,536; 6,517,868; 6,440,458;6,387,404; 6,344,215; 6,342,250; 6,326,027; 6,319,520; 6,306,438;6,274,599; 6,254,887; 6,245,356; 6,245,351; 6,228,398; 6,221,399;6,210,714; 6,162,463; 6,159,501; 6,156,342; 6,153,623; 6,143,353;6,143,322; 6,132,772; 6,103,261; 6,074,674; 6,048,548; 6,039,980;6,034,085; 6,030,642; 6,024,982; 5,952,005; 5,885,616; 5,869,100;5,858,408; 5,795,882; 5,773,025; 5,681,585; 5,674,533; 5,656,295;5,656,291; 5,639,476; 5,614,218; 5,591,452; 5,589,190; 5,582,837;5,580,578; 5,549,912; 5,520,931; 5,512,293; 5,508,042; 5,500,227;5,484,607; 5,472,712; 5,451,409; 5,399,358; 5,378,474; 5,334,392;5,330,766; 5,314,697; 5,281,415; 5,262,164; 5,242,910; 5,229,135;5,202,128; 5,198,220; 5,196,202; 5,186,930; 5,173,299; 5,128,144;5,114,718; 5,084,267; 5,077,051; 5,047,248; and 5,043,165, and in U.S.Patent application No. 20090060994; 20090017127; 20090017126;20080318910; 20080312309; 20080305160; 20080299196; 20080299189;20080274181; 20080274177; 20080268057; 20080234352; 20080226713;20080221174; 20080206335; 20080138411; 20080124399; 20080124398;20080118556; 20080113025; 20080102121; 20080095853; 20080075785;20080075781; 20080070972; 20080069888; 20080069873; 20080063711;20080057123; 20080026052; 20080020039; 20080003281; 20070298101;20070275065; 20070275062; 20070264325; 20070219175; 20070207214;20070196500; 20070196396; 20070185218; 20070166375; 20070160663;20070149590; 20070148153; 20070128276; 20070122481; 20070077297;20070071819; 20070048377; 20070003617; 20060269603; 20060269601;20060251721; 20060240105; 20060233880; 20060228413; 20060210631;20060210630; 20060204578; 20060193912; 20060193911; 20060165808;20060165807; 20060165792; 20060165791; 20060147527; 20060128806;20060110463; 20060099262; 20060099261; 20060073204; 20060068009;20060057203; 20060024366; 20050244498; 20050106247; 20040213844;20040197405; 20040132826; 20040122104; 20040076665; 20040052851;20030170304; 20030129237 and 20020054907, all of which are herebyincorporated in their entirety by reference.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, POLYOX WSR 301, Hypromellose K4M,Microcrystalline Cellulose 102, Talc, Magnesium Stearate, Siliconedioxide.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, POLYOX WSR 301, Hypromellose K4M,Microcrystalline Cellulose 102, Talc, Magnesium Stearate, Siliconedioxide.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, Microcrystalline cellulose 101, HypromelloseK100M, Ethyl cellulose N7, Talc, Aerosil 200, Carbopol 71G.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, POLYOX WSR 301, Hypromellose K4M,Microcrystalline cellulose 101, Talc, Magnesium Stearate, Siliconedioxide.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, POLYOX WSR 301, Hypromellose K4M,Microcrystalline cellulose 101, Talc, Magnesium Stearate, Siliconedioxide.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, POLYOX WSR 301, Hypromellose K4M,Microcrystalline cellulose 101, BTH EP, Talc, Magnesium Stearate,Silicone dioxide.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, Glyceryl Behenate (Melted), Cetyl Alcohol(Melted), Avicel PH 101, Talc, Mg. Stearate, Avicel PH 101.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, Polyox WSR 301, MCC 101, Talc, Mg. Stearate,SiO2.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, Polyox WSR 301, MCC 101, Talc, Mg. Stearate,SiO2.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, Polyox WSR 301, HPMC K100 M CR, MCC 102, Talc,Mg. Stearate, SiO2.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, Polyox WSR 301, HPMC K4 M, MCC 102, Talc, Mg.Stearate, SiO2.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, Polyox WSR 301, HPMC K100 M, HPMC K4 M, MCC102, Talc, Mg. Stearate, and SiO2.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, Mannitol, Lactose, and PVP K 30 in IPA 3 ml,Mg. Stearate, Talc, and Aerosil 200.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof, Sodium Chloride, Lactose, and PVP K 30 in IPA 3ml, Mg. Stearate, Talc, and Aerosil 200.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, POLYOX WSR 301, Hypromellose K4M, Microcrystalline Cellulose102, Talc, Magnesium Stearate, Silicone dioxide.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, POLYOX WSR 301, Hypromellose K4M, Microcrystalline Cellulose102, Talc, Magnesium Stearate, Silicone dioxide.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, Microcrystalline cellulose 101, Hypromellose K100M, Ethylcellulose N7, Talc, Aerosil 200, Carbopol 71G.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, POLYOX WSR 301, Hypromellose K4M, Microcrystalline cellulose101, Talc, Magnesium Stearate, Silicone dioxide.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, POLYOX WSR 301, Hypromellose K4M, Microcrystalline cellulose101, Talc, Magnesium Stearate, Silicone dioxide.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, POLYOX WSR 301, Hypromellose K4M, Microcrystalline cellulose101, BTH EP, Talc, Magnesium Stearate, Silicone dioxide.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, Glyceryl Behenate (Melted), Cetyl Alcohol (Melted), Avicel PH101, Talc, Mg. Stearate, Avicel PH 101.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, Polyox WSR 301, MCC 101, Talc, Mg. Stearate, and SiO2.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, Polyox WSR 301, MCC 101, Talc, Mg. Stearate, and SiO2.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, Polyox WSR 301, HPMC K100 M CR, MCC 102, Talc, Mg. Stearate, andSiO2.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, Polyox WSR 301, HPMC K4 M, MCC 102, Talc, Mg. Stearate, andSiO2.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, Polyox WSR 301, HPMC K100 M, HPMC K4 M, MCC 102, Talc, Mg.Stearate, and SiO2.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, Mannitol, Lactose, PVP K 30 in IPA 3 ml, Mg. Stearate, Talc, andAerosil 200.

In certain preferred embodiments of the present invention, the dosageform may comprise, in addition to butorphanol or a pharmaceuticallyacceptable salt thereof and a pH sensitive polymer overcoat describedherein, Sodium Chloride, Lactose, PVP K 30 in IPA 3 ml, Mg. Stearate,Talc, and Aerosil 200.

Matrix-Based Dosage Forms

In some embodiments, the modified release formulations of the presentinvention are provided as matrix-based dosage forms. Matrix formulationsaccording to the invention may include hydrophilic, e.g., water-soluble,and/or hydrophobic, e.g., water-insoluble, polymers. The matrixformulations of the present invention may optionally be prepared withfunctional coatings, which may be enteric, e.g., exhibiting apH-dependent solubility, or non-enteric, e.g., exhibiting apH-independent solubility.

Matrix formulations of the present invention may be prepared by using,for example, direct compression or wet granulation. A functionalcoating, as noted above, may then be applied in accordance with theinvention. Additionally, a barrier or sealant coat may be applied over amatrix tablet core prior to application of a functional coating. Thebarrier or sealant coat may serve the purpose of separating an activeingredient from a functional coating, which may interact with the activeingredient, or it may prevent moisture from contacting the activeingredient.

In a matrix-based dosage form in accordance with the present invention,the butorphanol and optional pharmaceutically acceptable excipient(s)are dispersed within a polymeric matrix, which typically comprises oneor more water-soluble polymers and/or one or more water-insolublepolymers. The drug may be released from the dosage form by diffusionand/or erosion.

In one embodiment, a matrix-based dosage form comprises butorphanol, afiller such as starch, lactose, or microcrystalline cellulose; acontrolled-release polymer, such as hydroxypropyl methylcellulose orpolyvinyl pyrrolidone; a disintegrant, such crospovidone, or starch; alubricant, such as magnesium stearate or stearic acid; a surfactant,such as sodium lauryl sulfate or polysorbates; and a glidant, such ascolloidal silicon dioxide or talc. The amounts and types of polymers,and the ratio of water-soluble polymers to water-insoluble polymers inthe inventive formulations are generally selected to achieve a desiredrelease profile of butorphanol. For example, by increasing the amount ofwater insoluble-polymer relative to the amount of water soluble-polymer,the release of the drug may, in some embodiments, be delayed or slowed.This is due, in part, to an increased impermeability of the polymericmatrix, and, in some cases, to a decreased rate of erosion duringtransit through the GI tract.

The controlled-release dosage form may optionally include a controlledrelease material which is incorporated into a matrix along with thebutorphanol, or which is applied as a sustained release coating over asubstrate comprising the drug (the term “substrate” encompassing beads,pellets, spheroids, tablets, tablet cores, etc). The controlled releasematerial may be hydrophobic or hydrophilic as desired. The oral dosageform according to the invention may be provided as, for example,granules, spheroids, pellets or other multiparticulate formulations. Anamount of the multiparticulates which is effective to provide thedesired dose of butorphanol over time may be placed in a capsule or maybe incorporated in any other suitable oral solid form, e.g., compressedinto a tablet. On the other hand, the oral dosage form according to thepresent invention may be prepared as a tablet core coated with acontrolled-release coating, or as a tablet comprising a matrix of drugand controlled release material, and optionally other pharmaceuticallydesirable ingredients (e.g., diluents, binders, colorants, lubricants,etc.). The controlled release dosage form of the present invention mayalso be prepared as a bead formulation or an osmotic dosage formulation.

In certain preferred embodiments of the present invention, thecontrolled-release formulation is achieved via a matrix (e.g. a matrixtablet) which includes a controlled-release material as set forth below.A dosage form including a controlled-release matrix provides in-vitrodissolution rates of butorphanol within the preferred ranges and thatreleases the butorphanol in a pH-dependent or pH-independent manner. Thematerials suitable for inclusion in a controlled-release matrix willdepend on the method used to form the matrix. The oral dosage form maycontain between 1% and 99% (by weight) of at least one hydrophilic orhydrophobic controlled release material.

A non-limiting list of suitable controlled-release materials which maybe included in a controlled-release matrix according to the inventioninclude hydrophilic and/or hydrophobic materials, such as gums,cellulose ethers, acrylic resins, protein derived materials, waxes,shellac, and oils such as hydrogenated castor oil, hydrogenatedvegetable oil hydrogenated Type I or Type II vegetable oils,polyoxyethylene stearates and distearates, glycerol monostearate, andnon-polymeric, non-water soluble liquids carbohydrate-based substancesor poorly water soluble, high melting point (mp=40 to 100° C.) waxes andmixtures thereof.

Hydrogenated vegetable oils of the present invention may includehydrogenated cottonseed oil (e.g., Akofine®; Lubritab®; Sterotex® NF),hydrogenated palm oil (Dynasan® P60; Softisan® 154), hydrogenatedsoybean oil (Hydrocote®; Lipovol HS-K®; Sterotex® HM) and hydrogenatedpalm kernel oil (e.g., Hydrokote® 112).

Polyoxyethylene stearates and distearates of the present inventioninclude Polyoxyl 2, 4, 6, 8, 12, 20, 30, 40, 50, 100 and 150 stearates(e.g., Hodag® DGS; PEG-2 stearate; Acconon® 200-MS; Hodag® 20-S; PEG-4stearate; Cerasynt® 616; Kessco® PEG 300 Monostearate; Acconon® 400-MS;Cerasynt® 660; Cithrol® 4MS; Hodag® 60-S; Kessco® PEG 600 Monostearate;Cerasynt® 840; Hodag 100-S; Myrj® 51; PEG-30 stearate; polyoxyethylene(30) stearate; Crodet® S40; E431; Emerest® 2672; Atlas G-2153; Crodet®S50) and polyoxyl 4, 8, 12, 32 and 150 distearates (e.g, Lipo-PEG®100-S; Myrj® 59; Hodag® 600-S; Ritox® 59; Hodag® 22-S; PEG-4 distearate;Hodag® 42-S; Kessco® PEG 400 DS; Hodag® 62-S; Kessco® PEG 600Distearate; Hodag® 154-S; Kessco® PEG 1540 Distearate; Lipo-PEG®6000-DS; Protamate® 6000-DS).

In one embodiment of the present invention, the butorphanol is combinedwith beeswax, hydroxypropyl methyl cellulose (e.g, HPMC K15M), silicondioxide (alone or in combination with Al₂O₃; e.g, Aerosil®, Aerosil®200, Aerosil® COK84).

In one embodiment of the present invention, the butorphanol is combinedwith hydrogenated cottonseed oil (e.g., Sterotex® NF), hydroxypropylmethyl cellulose (e.g, HPMC K15M), coconut oil and silicon dioxide(alone or in combination with Al₂O₃; e.g, Aerosil®, Aerosil® 200,Aerosil® COK84).

In another embodiment of the present invention, the butorphanol iscombined with glycerol monostearate (e.g., Cithrol® GMS), hydroxypropylmethyl cellulose (e.g, HPMC K100M) and silicon dioxide (alone or incombination with Al₂O₃; e.g, Aerosil®, Aerosil® 200, Aerosil® COK84).

In yet another embodiment of the present invention, the butorphanol iscombined with hydrogenated palm kernel oil (e.g., Hydrokote® 112),hydroxypropyl methyl cellulose (e.g, HPMC K15M) and silicon dioxide(alone or in combination with Al₂O₃; e.g, Aerosil®, Aerosil® 200,Aerosil® COK84).

In one embodiment of the present invention, release rate modifiers,including hydroxypropyl methyl cellulose (e.g, HPMC K15M) mayincorporated. Release rate modifiers can also have additional usefulproperties that optimize the formulation.

A variety of agents may be incorporated into the invention asthixotropes (e.g., fumed silicon dioxides, Aerosil®, Aerosil® COK84,Aerosil® 200, etc.). Thixotropes enhance the pharmaceutical formulationsof the invention by increasing the viscosity of solutions complementingthe action of HPMCs.

Any pharmaceutically acceptable hydrophobic or hydrophiliccontrolled-release material which is capable of impartingcontrolled-release of the butorphanol may be used in accordance with thepresent invention. Preferred controlled-release polymers includealkylcelluloses such as ethylcellulose, acrylic and methacrylic acidpolymers and copolymers, and cellulose ethers, especiallyhydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose) andcarboxyalkylcelluloses. Preferred acrylic and methacrylic acid polymersand copolymers include methyl methacrylate, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate,aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylicacid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate),poly(methacrylic acid) (anhydride), polymethacrylate, polyacrylamide,poly(methacrylic acid anhydride), glycidyl methacrylate copolymers,ethylcellulose, cellulose acetate cellulose propionate, celluloseacetate propionate, cellulose acetate butyrate, cellulose acetatephthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethylmethacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate),and poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecylacrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene)high density, poly(ethylene oxide), poly(ethylene terephthalate),poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) orpolyurethane, and/or mixtures thereof. Certain preferred embodimentsutilize mixtures of any of the foregoing controlled-release materials inthe matrices of the invention.

The matrix also may include a binder. In such embodiments, the binderpreferably contributes to the controlled-release of the butorphanol fromthe controlled-release matrix.

Preferred hydrophobic binder materials are water-insoluble with more orless pronounced hydrophilic and/or hydrophobic trends. Preferredhydrophobic binder materials which may be used in accordance with thepresent invention include digestible, long chain (C₈-C₅₀, especiallyC₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such as fattyacids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils, natural and synthetic waxes and polyalkylene glycols.Preferably, the hydrophobic binder materials useful in the inventionhave a melting point from about 30 to about 200° C., preferably fromabout 45 to about 90° C. When the hydrophobic material is a hydrocarbon,the hydrocarbon preferably has a melting point of between 25 and 90° C.Of the long chain (C₈-C₅₀) hydrocarbon materials, fatty (aliphatic)alcohols are preferred. The oral dosage form may contain up to 98% (byweight) of at least one digestible, long chain hydrocarbon.

The oral dosage form contains up to 98% (by weight) of at least onepolyalkylene glycol. The hydrophobic binder material may comprisenatural or synthetic waxes, fatty alcohols (such as lauryl, myristyl,stearyl, cetyl or preferably cetostearyl alcohol), fatty acids,including but not limited to fatty acid esters, fatty acid glycerides(mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons,normal waxes, stearic acid, stearyl alcohol and hydrophobic andhydrophilic materials having hydrocarbon backbones. Suitable waxesinclude, for example, beeswax, glycowax, castor wax and carnauba wax.For purposes of the present invention, a wax-like substance is definedas any material which is normally solid at room temperature and has amelting point of from about 30 to about 100° C.

In certain preferred embodiments, a combination of two or morehydrophobic binder materials are included in the matrix formulations. Ifan additional hydrophobic binder material is included, it is preferablyselected from natural and synthetic waxes, fatty acids, fatty alcohols,and mixtures of the same. Examples include beeswax, carnauba wax,stearic acid and stearyl alcohol. This list is not meant to beexclusive.

One particular suitable controlled-release matrix comprises at least onewater soluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferablyC₁₄-C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol. The hydroxyalkyl cellulose is preferably a hydroxy (C₁ to C₆)alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose.The amount of the at least one hydroxyalkyl cellulose in the presentoral dosage form will be determined, inter alia, by the precise rate ofthe butorphanol release required. The aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. Inparticularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol orcetostearyl alcohol. The amount of aliphatic alcohol in the present oraldosage form will be determined, as above, by the precise rate of thebutorphanol release required. It will also depend on whether at leastone polyalkylene glycol is present in or absent from the oral dosageform. In the absence of at least one polyalkylene glycol, the oraldosage form preferably contains between 20% and 50% (by wt) of thealiphatic alcohol. When a polyalkylene glycol is present in the oraldosage form, then the combined weight of the aliphatic alcohol and thepolyalkylene glycol preferably constitutes between 20% and 50% (by wt)of the total dosage.

In one preferred embodiment, the ratio of, e.g., the at least onehydroxyalkyl cellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the butorphanol from the formulation. A ratio of thehydroxyalkyl cellulose to the aliphatic alcohol/polyalkylene glycol ofbetween 1:2 and 1:4 is preferred, with a ratio of between 1:3 and 1:4being particularly preferred.

The polyalkylene glycol maybe, for example, polypropylene glycol or,which is preferred, polyethylene glycol. The number average molecularweight of the at least one polyalkylene glycol is preferred between1,000 and 15,000 especially between 1,500 and 12,000.

Another suitable controlled-release matrix comprises an alkylcellulose(especially ethylcellulose), a C₁₂ to C₃₆ aliphatic alcohol and,optionally, a polyalkylene glycol.

Another method of producing the dosage form of the invention involvesliquid fill compositions, including hydrogenated Type I or Type IIvegetable oils (e.g., Hydrokote® 112), polyoxyethylene stearates anddistearates, glycerol monostearate (e.g., Cithrol® GMS), non-polymeric,non-water soluble liquids carbohydrate-based substances, poorly watersoluble, high melting point (mp=40 to 100° C.) waxes.

Hydrogenated vegetable oils may include hydrogenated cottonseed oil(e.g., Akofine®; Lubritab®; Sterotex® NF), hydrogenated palm oil(Dynasan® P60; Softisan® 154), hydrogenated soybean oil (Hydrocote®;Lipovol HS-K®; Sterotex® HM) and hydrogenated palm kernel oil (e.g.,Hydrokote® 112).

Polyoxyethylene stearates and distearates may include Polyoxyl 2, 4, 6,8, 12, 20, 30, 40, 50, 100 and 150 stearates (e.g., Hodag® DGS; PEG-2stearate; Acconon® 200-MS; Hodag® 20-S; PEG-4 stearate; Cerasynt® 616;Kessco® PEG 300 Monostearate; Acconon® 400-MS; Cerasynt® 660; Cithrol®4MS; Hodag® 60-S; Kessco® PEG 600 Monostearate; Cerasynt® 840; Hodag100-S; Myrj® 51; PEG-30 stearate; polyoxyethylene (30) stearate; Crodet®S40; E431; Emerest® 2672; Atlas G-2153; Crodet® S50) and polyoxyl 4, 8,12, 32 and 150 distearates (e.g, Lipo-PEG® 100-S; Myrj® 59; Hodag®600-S; Ritox® 59; Hodag® 22-S; PEG-4 distearate; Hodag® 42-S; Kessco®PEG 400 DS; Hodag® 62-S; Kessco® PEG 600 Distearate; Hodag® 154-S;Kessco® PEG 1540 Distearate; Lipo-PEG® 6000-DS; Protamate® 6000-DS).

In one embodiment of the present invention, release rate modifiers,including hydroxypropyl methyl cellulose (e.g, HPMC K15M) may beincorporated. Release rate modifiers can also have additional usefulproperties that optimize the formulation.

A variety of agents may be incorporated into the invention asthixotropes (e.g., fumed silicon dioxides, Aerosil®, Aerosil® COK84,Aerosil® 200, etc.). Thixotropes enhance the pharmaceutical formulationsof the invention by increasing the viscosity of solutions duringattempted extraction, complementing the action of HPMCs. They may alsoprovide a tamper resistance by helping to retain the structure of dosageunits that have been heated to temperatures greater than the meltingpoint of the base excipient (Aerosils are unaffected by heat).

In addition to the above ingredients, a controlled-release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

In order to facilitate the preparation of a solid, controlled-releaseoral dosage form according to the invention there is provided, in afurther aspect of the present invention, a process for the preparationof a solid, controlled-release oral dosage form according to the presentinvention comprising incorporating the butorphanol or a salt thereof ina controlled-release matrix. Incorporation in the matrix may beeffected, for example, by (a) forming granules comprising at least onehydrophobic and/or hydrophilic material as set forth above (e.g., awater soluble hydroxyalkyl cellulose) together with the butorphanol; (b)mixing the at least one hydrophobic and/or hydrophilicmaterial-containing granules with at least one C₁₂-C₃₆ aliphaticalcohol, and (c) optionally, compressing and shaping the granules.

The granules may be formed by any of the procedures well-known to thoseskilled in the art of pharmaceutical formulation. For example, in onepreferred method, the granules may be formed by wet granulatinghydroxyalkyl cellulose/butorphanol with water. In a particular preferredembodiment of this process, the amount of water added during the wetgranulation step is preferably between 1.5 and 5 times, especiallybetween 1.75 and 3.5 times, the dry weight of the butorphanol.

In certain embodiments, the dosage form comprises a plurality ofmatrices described above.

The matrices of the present invention may also be prepared via a meltpellitization technique. In such circumstance, the butorphanol in finelydivided form is combined with a binder (also in particulate form) andother optional inert ingredients, and thereafter the mixture ispelletized, e.g., by mechanically working the mixture in a high shearmixer to form the pellets (granules, spheres). Thereafter, the pellets(granules, spheres) may be sieved in order to obtain pellets of therequisite size. The binder material is preferably in particulate formand has a melting point above about 40° C. Suitable binder substancesinclude, for example, hydrogenated castor oil, hydrogenated vegetableoil, other hydrogenated fats, fatty alcohols, fatty acid esters, fattyacid glycerides, and the like.

Controlled-release matrices can also be prepared by, e.g.,melt-granulation or melt-extrusion techniques. Generally,melt-granulation techniques involve melting a normally solid hydrophobicbinder material, e.g. a wax, and incorporating a powdered drug therein.To obtain a controlled release dosage form, it may be necessary toincorporate a hydrophobic controlled release material, e.g.ethylcellulose or a water-insoluble acrylic polymer, into the molten waxhydrophobic binder material.

The hydrophobic binder material may comprise one or more water-insolublewax-like thermoplastic substances possibly mixed with one or morewax-like thermoplastic substances being less hydrophobic than said oneor more water-insoluble wax-like substances. In order to achievecontrolled release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like binder substances may be those with awater-solubility that is lower than about 1:5,000 (w/w).

In addition to the above ingredients, a controlled release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art in amounts upto about 50% by weight of the particulate if desired. The quantities ofthese additional materials will be sufficient to provide the desiredeffect to the desired formulation.

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending thebutorphanol, together with a controlled release material and preferablya binder material to obtain a homogeneous mixture. The homogeneousmixture is then heated to a temperature sufficient to at least softenthe mixture sufficiently to extrude the same. The resulting homogeneousmixture is then extruded, e.g., using a twin-screw extruder, to formstrands. The extrudate is preferably cooled and cut intomultiparticulates by any means known in the art. The strands are cooledand cut into multiparticulates. The multiparticulates are then dividedinto unit doses. The extrudate preferably has a diameter of from about0.1 to about 5 mm and provides controlled release of the therapeuticallyactive agent for a time period of from about 6 to at least about 24hours.

An optional process for preparing the melt extrusioned formulations ofthe present invention includes directly metering into an extruder ahydrophobic controlled release material, a therapeutically active agent,and an optional binder material; heating the homogenous mixture;extruding the homogenous mixture to thereby form strands; cooling thestrands containing the homogeneous mixture; cutting the strands intoparticles having a size from about 0.1 mm to about 12 mm; and dividingsaid particles into unit doses. In this aspect of the invention, arelatively continuous manufacturing procedure is realized.

Plasticizers, such as those described herein, may be included inmelt-extruded matrices. The plasticizer is preferably included as fromabout 0.1 to about 30% by weight of the matrix. Other pharmaceuticalexcipients, e.g., talc, mono or poly saccharides, colorants, flavorants,lubricants and the like may be included in the controlled releasematrices of the present invention as desired. The amounts included willdepend upon the desired characteristic to be achieved.

The diameter of the extruder aperture or exit port can be adjusted tovary the thickness of the extruded strands. Furthermore, the exit partof the extruder need not be round; it can be oblong, rectangular, etc.The exiting strands can be reduced to particles using a hot wire cutter,guillotine, etc.

A melt extruded multiparticulate system can be, for example, in the formof granules, spheroids or pellets depending upon the extruder exitorifice. For purposes of the present invention, the terms “melt-extrudedmultiparticulate(s)” and “melt-extruded multiparticulate system(s)” and“melt-extruded particles” shall refer to a plurality of units,preferably within a range of similar size and/or shape and containingone or more active agents and one or more excipients, preferablyincluding a hydrophobic controlled release material as described herein.Preferably the melt-extruded multiparticulates will be of a range offrom about 0.1 to about 12 mm in length and have a diameter of fromabout 0.1 to about 5 mm. In addition, it is to be understood that themelt-extruded multiparticulates can be any geometrical shape within thissize range. Alternatively, the extrudate may simply be cut into desiredlengths and divided into unit doses of the therapeutically active agentwithout the need of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared that includean effective amount of melt-extruded multiparticulates within a capsule.For example, a plurality of the melt-extruded multiparticulates may beplaced in a gelatin capsule in an amount sufficient to provide aneffective controlled release dose when ingested and contacted by gastricfluid.

In another preferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, 21^(st) ed., 2005 incorporated by referenceherein.

In yet another preferred embodiment, the extrudate can be shaped intotablets as set forth in U.S. Pat. No. 4,957,681, hereby incorporated byreference.

Optionally, the controlled-release matrix multiparticulate systems ortablets can be coated, or the gelatin capsule can be further coated,with a controlled release coating such as the controlled releasecoatings described above. Such coatings preferably include a sufficientamount of hydrophobic and/or hydrophilic controlled-release material toobtain a weight gain level from about 2 to about 25 percent, althoughthe overcoat may be greater depending upon, e.g., the physicalproperties of the drug and the desired release rate, among other things.

The dosage forms of the present invention may further includecombinations of melt-extruded multiparticulates containing one or moredrugs. Furthermore, the dosage forms can also include an amount of animmediate release therapeutically active agent for prompt therapeuticeffect. The immediate release therapeutically active agent may beincorporated, e.g., as separate pellets within a gelatin capsule, or maybe coated on the surface of, e.g., melt extruded multiparticulates. Theunit dosage forms of the present invention may also contain acombination of, e.g., controlled release beads and matrixmultiparticulates to achieve a desired effect.

The controlled-release formulations of the present invention preferablyslowly release the therapeutically active agent, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. Thecontrolled-release profile of the melt-extruded formulations of theinvention can be altered, for example, by varying the amount ofcontrolled-release material, by varying the amount of plasticizerrelative to other matrix constituents, hydrophobic material, by theinclusion of additional ingredients or excipients, by altering themethod of manufacture, etc.

In other embodiments of the invention, melt-extruded formulations areprepared without the inclusion of the therapeutically active agent,which is added thereafter to the extrudate. Such formulations typicallywill have the therapeutically active agent blended together with theextruded matrix material, and then the mixture would be tableted inorder to provide a slow release formulation. Such formulations may beadvantageous, for example, when the therapeutically active agentincluded in the formulation is sensitive to temperatures needed forsoftening the hydrophobic material and/or the retardant material.

Typical melt-extrusion production systems suitable for use in accordancewith the present invention include a suitable extruder drive motorhaving variable speed and constant torque control, start-stop controls,and ammeter. In addition, the production system will include atemperature control console which includes temperature sensors, coolingmeans and temperature indicators throughout the length of the extruder.In addition, the production system will include an extruder such astwin-screw extruder which consists of two counter-rotating intermeshingscrews enclosed within a cylinder or barrel having an aperture or die atthe exit thereof. The feed materials enter through a feed hopper and aremoved through the barrel by the screws and are forced through the dieinto strands which are thereafter conveyed such as by a continuousmovable belt to allow for cooling and being directed to a pelletizer orother suitable device to render the extruded ropes into themultiparticulate system. The pelletizer can consist of rollers, fixedknife, rotating cutter and the like. Suitable instruments and systemswill be apparent to those of ordinary skill in the art.

A further aspect of the invention is related to the preparation ofmelt-extruded multiparticulates as set forth above in a manner whichcontrols the amount of air included in the extruded product. Bycontrolling the amount of air included in the extrudate, the releaserate of the therapeutically active agent from the, e.g.,multiparticulate extrudate, can be altered significantly. In certainembodiments, the pH dependency of the extruded product can be altered aswell.

Thus, in a further aspect of the invention, the melt-extruded product isprepared in a manner which substantially excludes air during theextrusion phase of the process. This may be accomplished, for example,by using a Leistritz extruder having a vacuum attachment. In certainpreferred embodiments the extruded multiparticulates prepared accordingto the invention using the Leistritz extruder under vacuum provides amelt-extruded product having different physical characteristics. Inparticular, the extrudate is substantially non-porous when magnified,e.g., using a scanning electron microscope which provides an SEM(scanning electron micrograph). Such substantially non-porousformulations provide a faster release of the therapeutically activeagent, relative to the same formulation prepared without vacuum. SEMs ofthe multiparticulates prepared using an extruder under vacuum appearvery smooth, and the multiparticulates tend to be more robust than thosemultiparticulates prepared without vacuum. In certain formulations, theuse of extrusion under vacuum provides an extruded multiparticulateproduct which is more pH-dependent than its counterpart formulationprepared without vacuum. Alternatively, the melt-extruded product isprepared using a Werner-Pfleiderer twin screw extruder.

In certain embodiments, a spheronizing agent is added to a granulate ormultiparticulates of the present invention and then spheronized toproduce controlled release spheroids. The spheroids are then optionallyovercoated with a controlled release coating by methods such as thosedescribed herein.

Spheronizing agents which may be used to prepare the multiparticulateformulations of the present invention include any art-known spheronizingagent. Cellulose derivatives are preferred, and microcrystallinecellulose is especially preferred. A suitable microcrystalline celluloseis, for example, the material sold as Avicel® PH 101. The spheronizingagent is preferably included as about 1 to about 99% of themultiparticulate by weight.

In addition to the active ingredient and spheronizing agent, thespheroids may also contain a binder. Suitable binders, such as lowviscosity, water soluble polymers, will be well known to those skilledin the pharmaceutical art. However, water soluble hydroxy loweralkylcellulose, such as hydroxypropylcellulose, are preferred.

In addition to the butorphanol and spheronizing agent, themultiparticulate formulations of the present invention may include acontrolled release material such as those described hereinabove.Preferred controlled-release materials for inclusion in themultiparticulate formulations include acrylic and methacrylic acidpolymers or copolymers, and ethylcellulose. When present in theformulation, the controlled-release material will be included in amountsof from about 1 to about 80% of the multiparticulate, by weight. Thecontrolled-release material is preferably included in themultiparticulate formulation in an amount effective to providecontrolled release of the butorphanol from the multiparticulate.

Pharmaceutical processing aids such as binders, diluents, and the likemay be included in the multiparticulate formulations. Amounts of theseagents included in the formulations will vary with the desired effect tobe exhibited by the formulation.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms of the present inventionare described in the Handbook of Pharmaceutical Excipients, APhAPublications; 5 edition (Jan. 5, 2006) incorporated by reference herein.

The multiparticulates may be overcoated with a controlled-releasecoating including a controlled-release material such as those describedhereinabove. The controlled-release coating is applied to a weight gainof from about 5 to about 30%. The amount of the controlled-releasecoating to be applied will vary according to a variety of factors, e.g.,the composition of the multiparticulate and the chemical and/or physicalproperties of the drug.

Matrix multiparticulates may also be prepared by granulating thespheronizing agent together with the butorphanol, e.g. by wetgranulation. The granulate is then spheronized to produce the matrixmultiparticulates. The matrix multiparticulates are then optionallyovercoated with the controlled release coating by methods such as thosedescribed hereinabove.

Another method for preparing matrix multiparticulates, for example, by(a) forming granules comprising at least one water soluble hydroxyalkylcellulose and the butorphanol or the butorphanol salt; (b) mixing thehydroxyalkyl cellulose containing granules with at least one C₁₂-C₃₆aliphatic alcohol; and (c) optionally, compressing and shaping thegranules. Preferably, the granules are formed by wet granulating thehydroxyalkyl cellulose/butorphanol with water. In a particularlypreferred embodiment of this process, the amount of water added duringthe wet granulation step is preferably between 1.5 and 5 times,especially between 1.75 and 3.5 times, the dry weight of thebutorphanol.

In yet other alternative embodiments, a spheronizing agent, togetherwith the active ingredient can be spheronized to form spheroids.Microcrystalline cellulose is preferred. A suitable microcrystallinecellulose is, for example, the material sold as Avicel® PH 101. In suchembodiments, in addition to the active ingredient and spheronizingagent, the spheroids may also contain a binder. Suitable binders, suchas low viscosity, water soluble polymers, will be well known to thoseskilled in the pharmaceutical art. However, water soluble hydroxy loweralkyl cellulose, such as hydroxy propyl cellulose, are preferred.Additionally (or alternatively) the spheroids may contain a waterinsoluble polymer, especially an acrylic polymer, an acrylic copolymer,such as a methacrylic acid-ethyl acrylate co-polymer, or ethylcellulose. In such embodiments, the sustained-release coating willgenerally include a water insoluble material such as (a) a wax, eitheralone or in admixture with a fatty alcohol; or (b) shellac or zein.

Spheroids of the present invention comprise a matrix formulation asdescribed above or bead formulation as described hereinafter having adiameter of between 0.1 mm and 2.5 mm, especially between 0.5 mm and 2mm.

The spheroids are preferably film coated with a controlled releasematerial that permits release of the butorphanol (or salt) at acontrolled rate in an aqueous medium. The film coat is chosen so as toachieve, in combination with the other stated properties, the in-vitrorelease rate outlined above (e.g., at least about 12.5% released after 1hour). The controlled-release coating formulations of the presentinvention preferably produce a strong, continuous film that is smoothand elegant, capable of supporting pigments and other coating additives,non-toxic, inert, and tack-free.

Preparation of Coated Bead Formulations

In certain preferred embodiments of the present invention the oral solidcontrolled release dosage form of the present invention comprises aplurality of coated substrates, e.g., inert pharmaceutical beads such asnu panel 18/20 beads. An aqueous dispersion of hydrophobic material isused to coat the beads to provide for the controlled release of thebutorphanol. In certain preferred embodiments a plurality of theresultant stabilized solid controlled-release beads may be placed in agelatin capsule in an amount sufficient to provide an effectivecontrolled-release dose when ingested and contacted by an environmentalfluid, e.g., gastric fluid or dissolution media.

The stabilized controlled-release bead formulations of the presentinvention slowly release the butorphanol, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. Thecontrolled-release profile of the formulations of the invention can bealtered, for example, by varying the amount of overcoating with theaqueous dispersion of hydrophobic controlled release material, alteringthe manner in which the plasticizer is added to the aqueous dispersionof hydrophobic controlled release material, by varying the amount ofplasticizer relative to hydrophobic controlled release material, by theinclusion of additional ingredients or excipients, by altering themethod of manufacture, etc. The dissolution profile of the ultimateproduct may also be modified, for example, by increasing or decreasingthe thickness of the controlled release coating.

Substrates coated with a therapeutically active agent are prepared, e.g.by dissolving the therapeutically active agent in water and thenspraying the solution onto a substrate, for example, nu panel 18/20beads, using a Wuster insert. Optionally, additional ingredients arealso added prior to coating the beads in order to assist the binding ofthe butorphanol to the beads, and/or to color the solution, etc. Forexample, a product which includes hydroxypropyl methylcellulose, etc.with or without colorant (e.g., Opadry®) may be added to the solutionand the solution mixed (e.g., for about 1 hour) prior to application ofthe same onto the substrate. The resultant coated substrate may then beoptionally overcoated with a barrier agent, to separate thetherapeutically active agent from the hydrophobic controlled-releasecoating.

An example of a suitable barrier agent is one which compriseshydroxypropyl methylcellulose. However, any film-former known in the artmay be used. It is preferred that the barrier agent does not affect thedissolution rate of the final product.

The substrates may then be overcoated with an aqueous dispersion of thehydrophobic controlled release material as described herein. The aqueousdispersion of hydrophobic controlled release material preferably furtherincludes an effective amount of plasticizer, e.g. triethyl citrate.Pre-formulated aqueous dispersions of ethylcellulose, such as Aquacoat®or Surelease®, may be used. If Surelease® is used, it is not necessaryto separately add a plasticizer. Alternatively, pre-formulated aqueousdispersions of acrylic polymers such as Eudragit® can be used.

The coating solutions of the present invention preferably contain, inaddition to the film-former, plasticizer, and solvent system (i.e.,water), a colorant to provide elegance and product distinction. Colormay be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color can be added to Aquacoat® via the use ofalcohol or propylene glycol based color dispersions, milled aluminumlakes and opacifiers such as titanium dioxide by adding color with shearto water soluble polymer solution and then using low shear to theplasticized Aquacoat®. Alternatively, any suitable method of providingcolor to dioxide and color pigments, such as iron oxide pigments. Theincorporation of pigments, may, however, increase the retard effect ofthe coating.

The plasticized aqueous dispersion of hydrophobic controlled releasematerial may be applied onto the substrate comprising thetherapeutically active agent by spraying using any suitable sprayequipment known in the art. In a preferred method, a Wursterfluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects drying while theacrylic polymer coating is sprayed on. A sufficient amount of theaqueous dispersion of hydrophobic material to obtain a predeterminedcontrolled-release of said therapeutically active agent when said coatedsubstrate is exposed to aqueous solutions, e.g. gastric fluid, ispreferably applied, taking into account the physical characteristics ofthe therapeutically active agent, the manner of incorporation of theplasticizer, etc. After coating with the hydrophobic controlled releasematerial, a further overcoat of a film-former, such as Opadry®, isoptionally applied to the beads. This overcoat is provided, if at all,in order to substantially reduce agglomeration of the beads.

Another method of producing controlled release bead formulationssuitable for about 24-hour administration is via powder layering. Thepowder-layered beads are prepared by spraying an aqueous binder solutiononto inert beads to provide a tacky surface, and subsequently spraying apowder that is a homogenous mixture of the butorphanol and hydrouslactose impalpable onto the tacky beads. The beads are then dried andcoated with a hydrophobic material such as those described hereinaboveto obtain the desired release of drug when the final formulation isexposed to environmental fluids. An appropriate amount of the controlledrelease beads are then, e.g. encapsulated to provide a final dosage formwhich provides effective plasma concentrations for the intended durationof effect or dosing frequency.

Controlled Release Osmotic Dosage

In another embodiment, the modified release formulations of the presentinvention are provided as osmotic pump dosage forms. In an osmotic pumpdosage form, a core containing the butorphanol and optionally one ormore osmotic excipients is typically encased by a selectively permeablemembrane having at least one orifice. The selectively permeable membraneis generally permeable to water, but impermeable to the drug. When thesystem is exposed to GI fluids, water penetrates through the selectivelypermeable membrane into the core containing the drug and optionalosmotic excipients. The osmotic pressure increases within the dosageform. Consequently, the drug is released through the orifice in anattempt to equalize the osmotic pressure across the selectivelypermeable membrane. In more complex pumps, the dosage form may containtwo internal compartments in the core. The first compartment containsthe drug and the second compartment may contain a polymer, which swellson contact with aqueous fluid. After ingestion, this polymer swells intothe drug-containing compartment, diminishing the volume occupied by thedrug, thereby delivering the drug from the device at a controlled rateover an extended period of time. Such dosage forms are often used when azero order release profile is desired.

Osmotic pumps are well known in the art. The osmotic pumps useful inaccordance with the present invention may be formed by compressing atablet of an osmotically active drug, or an osmotically inactive drug incombination with an osmotically active agent, and then coating thetablet with a selectively permeable membrane which is permeable to anexterior aqueous-based fluid but impermeable to the drug and/or osmoticagent.

One or more delivery orifices may be drilled through the selectivelypermeable membrane wall. Alternatively, one or more orifices in the wallmay be formed by incorporating leachable pore-forming materials in thewall. In operation, the exterior aqueous-based fluid is imbibed throughthe selectively permeable membrane wall and contacts the drug to form asolution or suspension of the drug. The drug solution or suspension isthen pumped out through the orifice as fresh fluid is imbibed throughthe selectively permeable membrane.

Typical materials for the selectively permeable membrane includeselectively permeable polymers known in the art to be useful in osmosisand reverse osmosis membranes, such as cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetate,cellulose triacetate, agar acetate, amylose triacetate, beta glucanacetate, acetaldehyde dimethyl acetate, cellulose acetate ethylcarbamate, polyamides, polyurethanes, sulfonated polystyrenes, celluloseacetate phthalate, cellulose acetate methyl carbamate, cellulose acetatesuccinate, cellulose acetate dimethyl aminoacetate, cellulose acetateethyl carbamate, cellulose acetate chloracetate, cellulose dipalmitate,cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanlate,cellulose acetate valerate, cellulose acetate succinate, cellulosepropionate succinate, methyl cellulose, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, lightly cross-linked polystyrenederivatives, cross-linked poly(sodium styrene sulfonate),poly(vinylbenzyltrimethyl ammonium chloride), cellulose acetate,cellulose diacetate, cellulose triacetate, and/or mixtures thereof.

The osmotic agents that can be used in the pump are typically soluble inthe fluid that enters the device following administration, resulting inan osmotic pressure gradient across the selectively permeable wallagainst the exterior fluid. Suitable osmotic agents include, but are notlimited to, magnesium sulfate, calcium sulfate, magnesium chloride,sodium chloride, lithium chloride, potassium sulfate, sodium carbonate,sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate,d-mannitol, urea, sorbitol, inositol, raffinose, sucrose, glucose,hydrophilic polymers such as cellulose polymers, and/or mixturesthereof.

The osmotic pump dosage form may contain a second compartment containinga swellable polymer. Suitable swellable polymers typically interact withwater and/or aqueous biological fluids, which causes them to swell orexpand to an equilibrium state. Acceptable polymers exhibit the abilityto swell in water and/or aqueous biological fluids, retaining asignificant portion of such imbibed fluids within their polymericstructure, so as into increase the hydrostatic pressure within thedosage form. The polymers may swell or expand to a very high degree,usually exhibiting a 2- to 40-fold volume increase. The polymers can benon-cross-linked or cross-linked. In one embodiment, the swellablepolymers are hydrophilic polymers. Suitable polymers include, but arenot limited to, poly(hydroxy alkyl methacrylate) having a molecularweight of from 30,000 to 5,000,000; kappa-carrageenan;polyvinylpyrrolidone having a molecular weight of from 10,000 to360,000; anionic and cationic hydrogels; polyelectrolyte complexes;poly(vinyl alcohol) having low amounts of acetate, cross-linked withglyoxal, formaldehyde, or glutaraldehyde, and having a degree ofpolymerization from 200 to 30,000; a mixture including methyl cellulose,cross-linked agar and carboxymethyl cellulose; a water-insoluble,water-swellable copolymer produced by forming a dispersion of finelydivided maleic anhydride with styrene, ethylene, propylene, butylene orisobutylene; water-swellable polymers of N-vinyl lactams; and/ormixtures of any of the foregoing.

The term “orifice” as used herein comprises means and methods suitablefor releasing the drug from the dosage form. The expression includes oneor more apertures orifices that have been bored through the selectivelypermeable membrane by mechanical procedures. Alternatively, an orificemay be formed by incorporating an erodible element, such as a gelatinplug, in the selectively permeable membrane. In such cases, the pores ofthe selectively permeable membrane form a “passageway” for the passageof the drug. Such passageway formulations are described in the art.

The osmotic pumps useful in accordance with this invention may bemanufactured by techniques known in the art. For example, the drug andother ingredients may be milled together and pressed into a solid havingthe desired dimensions (e.g., corresponding to the first compartment).The swellable polymer is then formed, placed in contact with the drug,and both are surrounded with the selectively permeable agent. Ifdesired, the drug component and polymer component may be pressedtogether before applying the selectively permeable membrane. Theselectively permeable membrane may be applied by any suitable method,for example, by molding, spraying, or dipping.

Controlled release dosage forms according to the present invention mayalso be prepared as osmotic dosage formulations. The osmotic dosageforms preferably include a bilayer core comprising a drug layer and adelivery or push layer, wherein the bilayer core is surrounded by asemipermeable wall and optionally having at least one passagewaydisposed therein. In certain embodiments, the bilayer core comprises adrug layer with the butorphanol or a salt thereof and a displacement orpush layer. In certain preferred embodiments the drug layer may alsocomprise at least one polymer hydrogel. The polymer hydrogel may have anaverage molecular weight of between about 500 and about 6,000,000.Examples of polymer hydrogels include but are not limited to amaltodextrin polymer comprising the formula (C₆H₁₂O₅)_(n). H2O, whereinn is 3 to 7,500, and the maltodextrin polymer comprises a 500 to1,250,000 number-average molecular weight; a poly(alkylene oxide)represented by, e.g., a poly(ethylene oxide) and a poly(propylene oxide)having a 50,000 to 750,000 weight-average molecular weight, and morespecifically represented by a poly(ethylene oxide) of at least one of100,000, 200,000, 300,000 or 400,000 weight-average molecular weights;an alkali carboxyalkylcellulose, wherein the alkali is sodium orpotassium, the alkyl is methyl, ethyl, propyl, or butyl of 10,000 to175,000 weight-average molecular weight; and a copolymer ofethylene-acrylic acid, including methacrylic and ethacrylic acid of10,000 to 500,000 number-average molecular weight.

In certain preferred embodiments of the present invention, the deliveryor push layer comprises an osmopolymer. Examples of an osmopolymerinclude but are not limited to a member selected from the groupconsisting of a polyalkylene oxide and a carboxyalkylcellulose. Thepolyalkylene oxide possesses a 1,000,000 to 10,000,000 weight-averagemolecular weight. The polyalkylene oxide may be a member selected fromthe group consisting of polymethylene oxide, polyethylene oxide,polypropylene oxide, polyethylene oxide having a 1,000,000 averagemolecular weight, polyethylene oxide comprising a 5,000,000 averagemolecular weight, polyethylene oxide comprising a 7,000,000 averagemolecular weight, cross-linked polymethylene oxide possessing a1,000,000 average molecular weight, and polypropylene oxide of 1,200,000average molecular weight. Typical osmopolymer carboxyalkylcellulosecomprises a member selected from the group consisting of alkalicarboxyalkylcellulose, sodium carboxymethylcellulose, potassiumcarboxymethylcellulose, sodium carboxyethylcellulose, lithiumcarboxymethylcellulose, sodium carboxyethylcellulose,carboxyalkylhydroxyalkylcellulose, carboxymethylhydroxyethyl cellulose,carboxyethylhydroxyethylcellulose andcarboxymethylhydroxypropylcellulose. The osmopolymers used for thedisplacement layer exhibit an osmotic pressure gradient across thesemipermeable wall. The osmopolymers imbibe fluid into dosage form,thereby swelling and expanding as an osmotic hydrogel (also known asosmogel), whereby they push the butorphanol or pharmaceuticallyacceptable salt thereof from the osmotic dosage form.

The push layer may also include one or more osmotically effectivecompounds also known as osmagents and as osmotically effective solutes.They imbibe an environmental fluid, for example, from thegastrointestinal tract, into dosage form and contribute to the deliverykinetics of the displacement layer. Examples of osmotically activecompounds comprise a member selected from the group consisting ofosmotic salts and osmotic carbohydrates. Examples of specific osmagentsinclude but are not limited to sodium chloride, potassium chloride,magnesium sulfate, lithium phosphate, lithium chloride, sodiumphosphate, potassium sulfate, sodium sulfate, potassium phosphate,glucose, fructose and maltose.

The push layer may optionally include a hydroxypropylalkylcelluloserepresented by a member selected from the group consisting ofhydroxypropylmethylcellulose, hydroxypropylethylcellulose, hydroxypropylisopropylcellulose, hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose.

The push layer optionally may comprise a nontoxic colorant or dye.Examples of colorants or dyes include but are not limited to Food andDrug Administration Colorant (FD&C), such as FD&C No. 1 blue dye, FD&CNo. 4 red dye, red ferric oxide, yellow ferric oxide, titanium dioxide,carbon black, and indigo.

The push layer which is devoid of butorphanol may also optionallycomprise an antioxidant to inhibit the oxidation of the excipients ofthe push layer. Some examples of antioxidants include but are notlimited to a member selected from the group consisting of ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodiumisoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate,sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E,4-chloro-2,6-ditertiarybutylphenol, alphatocopherol, and propylgallate.

In certain alternative embodiments, the dosage form comprises anhomogenous core comprising the butorphanol or a pharmaceuticallyacceptable salt thereof, a pharmaceutically acceptable polymer (e.g.,polyethylene oxide), optionally a disintegrant (e.g.,polyvinylpyrrolidone), optionally an absorption enhancer (e.g., a fattyacid, a surfactant, a chelating agent, a bile salt, etc.). Thehomogenous core is surrounded by a semipermeable wall having apassageway (as defined above) for the release of the butorphanol orpharmaceutically acceptable salt thereof.

In certain embodiments, the semipermeable wall comprises a memberselected from the group consisting of a cellulose ester polymer, acellulose ether polymer and a cellulose ester-ether polymer.Representative wall polymers comprise a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tricellulose alkenylates, and mono-, di- andtricellulose alkinylates. The poly(cellulose) used for the presentinvention comprises a number-average molecular weight of 20,000 to7,500,000.

Additional semipermeable polymers for the purpose of this inventioncomprise acetaldehyde dimethycellulose acetate, cellulose acetateethylcarbamate, cellulose acetate methylcarbamate, cellulose diacetate,propylcarbamate, cellulose acetate diethylaminoacetate; semipermeablepolyamide; semipermeable polyurethane; semipermeable sulfonatedpolystyrene; semipermeable cross-linked polymer formed by thecoprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,876;semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat.No. 3,133,132; semipermeable crosslinked polystyrenes; semipermeablecross-linked poly(sodium styrene sulfonate); semipermeable crosslinkedpoly(vinylbenzyltrimethyl ammonium chloride); and semipermeable polymerspossessing a fluid permeability of 2.5×10⁻⁸ to 2.5×10⁻² (cm²/hr·atm)expressed per atmosphere of hydrostatic or osmotic pressure differenceacross the semipermeable wall. Other polymers useful in the presentinvention are known in the art in U.S. Pat. Nos. 3,845,770; 3,916,899and 4,160,020; and in Handbook of Common Polymers, Scott, J. R. and W.J. Roff, 1971, CRC Press, Cleveland, Ohio.

In certain embodiments, preferably the semipermeable wall is nontoxic,inert, and it maintains its physical and chemical integrity during thedispensing life of the drug. In certain embodiments, the dosage formcomprises a binder as described above.

In certain embodiments, the dosage form comprises a lubricant, which maybe used during the manufacture of the dosage form to prevent sticking todie wall or punch faces. Examples of lubricants include but are notlimited to magnesium stearate, sodium stearate, stearic acid, calciumstearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid,sodium stearyl fumarate, and magnesium palmitate.

Coatings

The dosage forms of the present invention may optionally be coated withone or more coatings suitable for the regulation of release or for theprotection of the formulation. In one embodiment, coatings are providedto permit either pH-dependent or pH-independent release, e.g., whenexposed to gastrointestinal fluid. When a pH-independent coating isdesired, the coating is designed to achieve optimal release regardlessof pH-changes in the environmental fluid, e.g., the GI tract. Otherpreferred embodiments include a pH-dependent coating that releases thebutorphanol in desired areas of the gastrointestinal (GI) tract, e.g.,the stomach or small intestine, such that an absorption profile isprovided which is capable of providing at least about twelve hour andpreferably up to twenty-four hour analgesia to a patient. It is alsopossible to formulate compositions which release a portion of the dosein one desired area of the GI tract, e.g., the stomach, and release theremainder of the dose in another area of the GI tract, e.g., the smallintestine.

Formulations according to the invention that utilize pH-dependentcoatings may also impart a repeat-action effect whereby unprotected drugis coated over an enteric coat and is released in the stomach, while theremainder, being protected by the enteric coating, is released furtherdown the gastrointestinal tract. Coatings which are pH-dependent may beused in accordance with the present invention include a controlledrelease material such as, e.g., shellac, cellulose acetate phthalate(CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulosephthalate, and methacrylic acid ester copolymers, zein, and the like.

In another preferred embodiment, the present invention is related to astabilized solid controlled dosage form comprising the butorphanolcoated with a hydrophobic controlled release material selected from (i)an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.The coating may be applied in the form of an organic or aqueous solutionor dispersion.

In certain preferred embodiments, the controlled release coating isderived from an aqueous dispersion of the hydrophobic controlled releasematerial. The coated substrate containing the butorphanol (e.g., atablet core or inert pharmaceutical beads or spheroids) is then cureduntil an endpoint is reached at which the substrate provides a stabledissolution. The curing endpoint may be determined by comparing thedissolution profile (curve) of the dosage form immediately after curingto the dissolution profile (curve) of the dosage form after exposure toaccelerated storage conditions of, e.g., at least one month at atemperature of 40° C. and a relative humidity of 75%.

In preferred embodiments, the controlled release coatings include aplasticizer such as those described herein.

In certain embodiments, it is necessary to overcoat the substratecomprising the butorphanol with a sufficient amount of the aqueousdispersion of e.g., alkylcellulose or acrylic polymer, to obtain aweight gain level from about 2 to about 50%, e.g., about 2 to about 25%in order to obtain a controlled-release formulation. The overcoat may belesser or greater depending upon the physical properties of thetherapeutically active agent and the desired release rate, the inclusionof plasticizer in the aqueous dispersion and the manner of incorporationof the same, for example.

Alkylcellulose Polymers

Cellulosic materials and polymers, including alkylcelluloses arecontrolled release materials well suited for coating the substrates,e.g., beads, tablets, etc. according to the invention. Simply by way ofexample, one preferred alkylcellulosic polymer is ethylcellulose,although the artisan will appreciate that other cellulose and/oralkylcellulose polymers may be readily employed, singly or on anycombination, as all or part of a hydrophobic coating according to theinvention.

One commercially-available aqueous dispersion of ethylcellulose isAquacoat®. Aquacoat® is prepared by dissolving the ethylcellulose in awater-immiscible organic solvent and then emulsifying the same in waterin the presence of a surfactant and a stabilizer. After homogenizationto generate submicron droplets, the organic solvent is evaporated undervacuum to form a pseudolatex. The plasticizer is not incorporated in thepseudolatex during the manufacturing phase. Thus, prior to using thesame as a coating, it is necessary to intimately mix the Aquacoat® witha suitable plasticizer prior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease®. This product is prepared by incorporating plasticizerinto the dispersion during the manufacturing process. A hot melt of apolymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) isprepared as a homogeneous mixture, which is then diluted with analkaline solution to obtain an aqueous dispersion which can be applieddirectly onto substrates.

Acrylic Polymers

In other preferred embodiments of the present invention, the controlledrelease material comprising the controlled-release coating is apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate,poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamidecopolymer, poly(methyl methacrylate), polymethacrylate, poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), and glycidyl methacrylatecopolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers Ammonio methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In order to obtain a desirable dissolution profile, it may be necessaryto incorporate two or more ammonio methacrylate copolymers havingdiffering physical properties, such as different molar ratios of thequaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit®. There are severaldifferent types of Eudragit®. For example, Eudragit® E is an example ofa methacrylic acid copolymer which swells and dissolves in acidic media.Eudragit® L is a methacrylic acid copolymer which does not swell atabout pH<5.7 and is soluble at about pH>6. Eudragit® S does not swell atabout pH<6.5 and is soluble at about pH>7. Eudragit® RL and Eudragit® RSare water swellable, and the amount of water absorbed by these polymersis pH-dependent, however, dosage forms coated with Eudragit® RL and RSare pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available asEudragit® RL30D and Eudragit® RS30D, respectively. Eudragit® RL30D andEudragit® RS30D are copolymers of acrylic and methacrylic esters with alow content of quaternary ammonium groups, the molar ratio of ammoniumgroups to the remaining neutral (meth)acrylic esters being 1:20 inEudragit® RL30D and 1:40 in Eudragit® RS30D. The mean molecular weightis about 150,000. The code designations RL (high permeability) and RS(low permeability) refer to the permeability properties of these agents.Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids.However, coatings formed from the same are swellable and permeable inaqueous solutions and digestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain acontrolled-release formulation having a desirable dissolution profile.Desirable controlled-release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L.

Plasticizers

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic controlled release material, theinclusion of an effective amount of a plasticizer in the aqueousdispersion of hydrophobic material will further improve the physicalproperties of the controlled-release coating. For example, becauseethylcellulose has a relatively high glass transition temperature anddoes not form flexible films under normal coating conditions, it ispreferable to incorporate a plasticizer into an ethylcellulose coatingcontaining controlled-release coating before using the same as a coatingmaterial. Generally, the amount of plasticizer included in a coatingsolution is based on the concentration of the film-former, e.g., mostoften from about 1 to about 50 percent by weight of the film-former.Concentration of the plasticizer, however, can only be properlydetermined after careful experimentation with the particular coatingsolution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tibutyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

In certain embodiments, the addition of a small amount of talc to thecontrolled release coating reduces the tendency of the aqueousdispersion to stick during processing, and acts as a polishing agent.

The release of the therapeutically active agent from thecontrolled-release formulation of the present invention can be furtherinfluenced, i.e., adjusted to a desired rate, by the addition of one ormore release-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic controlled releasematerial to water soluble material is determined by, among otherfactors, the release rate required and the solubility characteristics ofthe materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

The controlled-release coatings of the present invention can alsoinclude erosion-promoting agents such as starch and gums.

The controlled-release coatings of the present invention can alsoinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain.

The release-modifying agent may also comprise a semi-permeable polymer.In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The controlled-release coatings of the present invention may alsoinclude an exit means comprising at least one passageway, orifice, orthe like. The passageway may be formed by such methods as thosedisclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and4,088,864, all of which are hereby incorporated by reference. Thepassageway can have any shape such as round, triangular, square,elliptical, irregular, etc.

These and other embodiments of the present invention will readily occurto those of ordinary skill in the art in view of the disclosure herein.

A wide variety of materials can be used for preparing the dosage formaccording to this invention. This invention therefore contemplates theuse of materials other than those specifically disclosed herein,including those which may hereafter become known to the art to becapable of performing the necessary functions.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever. A wide variety of methods known in the art for thepreparation of oral immediate release and oral controlled release dosageforms may be incorporated into the invention. Other suitable dosageforms may also be prepared by modification of the examples herein and byuse of material other than those specifically disclosed herein,including those which may hereafter become known to the art to becapable of performing the necessary functions. Other suitablemodifications and adaptations of the variety of conditions andparameters normally encountered and obvious to those skilled in the artare within the spirit and scope of the invention.

The percent loading of the butorphanol onto the dosage form may bevaried depending on the physiochemical and pharmaceutical properties ofimmediate release and controlled release material, excipients, theselected salt of butorphanol and the desired release profile andduration of actions.

The ingredients used for the preparation of the butorphanol dosage formagent may be modified depending on the selection, dose and desiredduration of effect. In some embodiments, a change in the dose or amountbutorphanol will not require a significant change in amount of otheringredients. In other embodiments, a proportional change in the amountof other ingredients is required to maintain the desired properties. Inyet other embodiments, a change in the dose or amount butorphanolnecessitates a change in the nature and/or amount of ingredients toprovide the required characteristics of the butorphanol (e.g., durationof effect, rate and extent of absorption, therapeutic concentrations andeffect, etc.).

A wide variety of formulations of modified release butorphanol have beenprepared and evaluated by the applicant.

EXAMPLES Example 1

Tablet Composition of Extended Release Butorphanol Tartrate IngredientsQty./Unit 1. Butorphanol Tartrate 20 mg 2. HPMC 2208, USP 150 mg 3.Carnauba wax 30 mg 4. HPMC 2910, USP 15 mg 5. Magnesium Stearate 2 mg 6.Stearic acid 8 mg 7. Talc 3 mg

Place the ingredients 1, 2 and 3 in the granulator and mix for 15minutes. Dissolve ingredient 4 in water (mix in hot water, then cooldown) and spray into the fluidized mixture. Dry to approximately 5%moisture. Sequentially add ingredient 5, 6 and 7, with mixing stepsbetween each addition. Compress using capsule shaped tooling.

Example 2

Tablet Composition of Extended Release Butorphanol Tartrate IngredientsQty./Unit 1. Butorphanol Tartrate 100 mg 2. HPMC 2208, USP 250 mg 3.Carnauba wax 50 mg 4. HPMC 2910, USP 25 mg 5. Magnesium Stearate 4 mg 6.Stearic acid 14 mg 7. Talc 5 mg

Place the ingredients 1, 2 and 3 in the granulator and mix for 15minutes. Dissolve ingredient 4 in water (mix in hot water, then cooldown) and spray into the fluidized mixture. Dry to approximately 5%moisture. Sequentially add ingredient 5, 6 and 7, with mixing stepsbetween each addition. Compress using capsule shaped tooling.

Example 3

Tablet Composition of Extended Release Butorphanol Tartrate IngredientsQty./Unit 1. Butorphanol Tartrate 500 mg 2. HPMC 2208, USP 250 mg 3.Carnauba wax 50 mg 4. HPMC 2910, USP 25 mg 5. Magnesium Stearate 4 mg 6.Stearic acid 14 mg 7. Talc 5 mg

Place the ingredients 1, 2 and 3 in the granulator and mix for 15minutes. Dissolve ingredient 4 in water (mix in hot water, then cooldown) and spray into the fluidized mixture. Dry to approximately 5%moisture. Sequentially add ingredient 5, 6 and 7, with mixing stepsbetween each addition. Compress using capsule shaped tooling.

Example 4

Tablet Composition of Extended Release Butorphanol Base IngredientsAmt/Unit (mg) Butorphanol Base 20 Spray Dried Lactose 60 Povidone 5Eudragit RS30D (solids) 10 Triacetin 2 Stearyl Alcohol 25 Talc 2.5Magnesium Stearate 1.25 Opadry Pink Y-S-14518A 4.0

1. Granulation: Spray the Eudragit/Triacetin dispersion onto theButorphanol, Spray Dried Lactose and Povidone using a fluid bedgranulator. 2. Milling: Discharge the granulation and pass through amill. 3. Waxing: Melt the stearyl alcohol and add to the milledgranulation using a mixer. Allow to cool. 4. Milling: Pass the cooledgranulation through a mill 5 Lubrication: Lubricate the granulation withtalc and magnesium stearate using a mixer. 6. Compression: Compress thegranulation into tablets using a tablet press. 7. Film coating: Apply anaqueous film coat to the tablets.

Example 5

Tablet Composition of Extended Release Butorphanol Tartrate IngredientsAmt/Unit (mg) Butorphanol Tartrate 30 Spray Dried Lactose 60 Povidone 5Eudragit RS30D (solids) 10 Triacetin 2 Stearyl Alcohol 25 Talc 2.5Magnesium Stearate 1.25 Opadry Pink Y-S-14518A 4.0

1. Granulation: Spray the Eudragit/Triacetin dispersion onto theButorphanol, Spray Dried Lactose and Povidone using a fluid bedgranulator. 2. Milling: Discharge the granulation and pass through amill. 3. Waxing: Melt the stearyl alcohol and add to the milledgranulation using a mixer. Allow to cool. 4. Milling: Pass the cooledgranulation through a mill 5 Lubrication: Lubricate the granulation withtalc and magnesium stearate using a mixer. 6. Compression: Compress thegranulation into tablets using a tablet press. 7. Film coating: Apply anaqueous film coat to the tablets.

Example 6

Capsule Composition of Extended Release Butorphanol Base IngredientsAmt/Unit (mg) Butorphanol Base 20 Eudragit RSPO 76 Eudragit RLPO 4Stearyl Alcohol 25

1. Blend milled Stearyl Alcohol, Eudragit RLPO, Butorphanol, andEudragit RSPO using a Hobart Mixer. 2. Extrude the granulation using aPowder Feeder, Melt Extruder (equipped with the 6×1 mm die head),Conveyor, Lasermike, and Pelletizer. Powder feed rate—40 g/min;vacuum—about 980 mBar; Conveyor, such that diameter of extrudate is 1mm, Pelletizer, such that pellets are cut to 1 mm in length. Screenpellets using #16 mesh and #20 mesh screens. Collect material thatpasses through the #16 mesh screen and is retained on the #20 meshscreen. 4. Fill capsules with the pellets.

Example 7

Capsule Composition of Extended Release Butorphanol Base IngredientsAmt/Unit (mg) Butorphanol Base 200 Eudragit RSPO 150 Eudragit RLPO 10Stearyl Alcohol 40

1. Blend milled Stearyl Alcohol, Eudragit RLPO, Butorphanol, andEudragit RSPO using a Hobart Mixer. 2. Extrude the granulation using aPowder Feeder, Melt Extruder (equipped with the 6×1 mm die head),Conveyor, Lasermike, and Pelletizer. Powder feed rate—40 g/min;vacuum—about 980 mBar; Conveyor, such that diameter of extrudate is 1mm, Pelletizer, such that pellets are cut to 1 mm in length. Screenpellets using #16 mesh and #20 mesh screens. Collect material thatpasses through the #16 mesh screen and is retained on the #20 meshscreen. 4. Fill capsules with the pellets.

Example 8

Capsule Composition of Extended Release Butorphanol Base IngredientsAmt/Unit (mg) Butorphanol Base 15 Eudragit RSPO 77 Ethocel 4.5 Stearicacid 27

Blend milled Steam acid, Ethocel, Butorphanol Base, and Eudragit RSPOusing a V-blender. 2. Extrude the mixture using a Powder Feeder, MeltExtruder (equipped with the 6×1 mm die head), Conveyor, Lasermike, andPelletizer. Powder feed rate, 1.2 kg/hr; vacuum, about 980 mBar;Conveyor, such that diameter of extrudate is 1 mm; Pelletizer, such thatpellets are cut to 1 mm in length. 3. Screen pellets using #16 mesh and#20 mesh screens. Collect material that passes through the #16 meshscreen and is retained on the #20 mesh screen. Fill pellets in capsules.

Example 9

Capsule Composition of Extended Release Butorphanol Tartrate StepsIngredients Amt/unit (mg) 1 Butorphanol Tartrate 12 Non-pareil beads(30/35 mesh) 45 Opadry Clear 2.5 2 Eudragit RS3-D (dry) 7.2 EudragitRL30D (dry) 0.4 Triethyl citrate 1.5 Cabosil 0.4 3 Opadry Clear (HPMC)1.9 Cabosil 0.28

1. Dissolve Butorphanol Tartrate and Opadry (HPMC) in water. Spray thedrug solution onto nonpareil beads in a fluid bed coater with Wursterinsert. 2. Disperse Eudragit RS, Eudragit RL, triethyl citrate, andCabosil in water. Spray the dispersion onto the beads in the fluid bedcoater. 3. Dissolve Opadry in water. Spray the solution onto the beadsin the fluid bed coater. 4. Cure the beads at 60° C. for 24 hours.

Example 10

Tablet Composition of Extended Release Butorphanol Tartrate IngredientAmt/unit (mg) Butorphanol Tartrate 75 Anhydrous Dicalcium 60 Phosphate(Powdered) 80 Microcrystalline Cellulose 80 Glyceryl Behenate 40Magnesium Stearate  4 Opadry Red 17 Purified Water 900* *Remains inproduct as residual moisture only.

1. Pass the Stearyl Alcohol flakes through an oscillating mill 2 Mix theButorphanol Tartrate, milled Stearyl Alcohol, Anhydrous DicalciumPhosphate, Microcrystalline Cellulose, and Glyceryl Behenate in a twinshell blender. 3. Continuously feed the blended material into a twinscrew extruder and collect the resultant heated material on a conveyor.4. Allow the extrudate to cool on the conveyor. 5. Mill the cooledextrudate using an oscillating mill 6 Blend the milled extrudate andMagnesium Stearate. 7. Compress the resultant granulation using a tabletpress, preferably into a caplet. 8. Prepare a film coating solution bydispersing the Opadry in Purified Water and applying it to the tablet.

Example 11

Capsule Composition of Extended Release Butorphanol Tartrate IngredientAmt/unit (mg) Butorphanol Tartrate 20 Eudragit RSPO 76.5 Ethylcellulose4.5 Stearyl Alcohol 27

1. Pass Stearyl Alcohol flakes through an impact mill. 2. Mix theButorphanol Tartrate, Eudragit, Ethylcellulose and milled StearylAlcohol in a twin shell blender. 3. Continuously feed the blendedmaterial into a twin screw extruder and collect the resultant strands ona conveyor. 4. Allow the strands to cool on the conveyor. 5. Cut thecooled strands into pellets using a Pelletizer. 6. Screen the pelletsand collect desired sieve portion. 7. Fill the extruded pellets intocapsules.

Example 12 to 23 may be prepared as follows: (i) Dispense the specifiedhydrophobic controlled release material (e.g., hydrogenated Type Ivegetable oil, hydrogenated Type II vegetable oil, polyoxyethylenestearates, polyoxyethylene distearates, glycerol monostearate, poorlywater soluble, or high melting point waxes) into a mixer; (ii) Heatuntil fully melted; (iii) dispense the hydroxypropyl methyl cellulose(HPMC) into the mixer; (iv) Mix until dispersed; (v) Dispense theAerosil into the same vessel; (vi) Mix until dispersed; (vii) Dispensethe butorphanol into the same vessel; (viii) Stir thoroughly with a highshear mixer; (ix) Transfer the mix into a liquid filling machine; (x)Fill into hard gelatin (or HPMC) capsule; (xi) Optionally, transfer thecapsules to a banding machine and band the capsules.

Example 12

Capsule Composition of Extended Release Butorphanol Tartrate IngredientsQuantity (mg)/Dose Sterotex ® NF 200 Fractionated coconut oil 70Methocel ® K 15M 81 Aerosil ® COK 84 4 Butorphanol Tartrate 50

Example 13

Capsule Composition of Extended Release Butorphanol Tartrate IngredientsQuantity (mg)/Dose Beeswax 200 HPMC, K15M 80 Aerosil COK 84 8Butorphanol Tartrate 40

Example 14

Capsule Composition of Extended Release Butorphanol Base IngredientsQuantity (mg)/Dose Sterotex NF 150 HPMC, K15M 75 Coconut oil 75 AerosilCOK 84 5 Butorphanol 100

Example 15

Capsule Composition of Extended Release Butorphanol Base IngredientsQuantity (mg)/Dose Cithrol GMS 275 HPMC, K100M 40 Aerosil COK 84 10Butorphanol 75

Example 16

Capsule Composition of Extended Release Butorphanol Tartrate IngredientsQuantity (mg)/Dose Hydrokote 112 250 HPMC, K15M 60 Aerosil COK 84 10Butorphanol Tartrate 150

Example 17

Capsule Composition of Extended Release Butorphanol Base IngredientsQuantity (mg)/Dose Beeswax 200 HPMC, Pharmacoat 606 62.5 Aerosil COK 847.5 Butorphanol Base 200

Example 18

Capsule Composition of Extended Release Butorphanol Base IngredientsQuantity (mg)/Dose Gelucire 50/02 190 Methocel K 100M 35 Aerosil COK 8410 Butorphanol Base 250

Example 19

Capsule Composition of Extended Release Butorphanol Base IngredientsQuantity (mg)/Dose Cetyl alcohol 280 Methocel K 100M 50 Aerosil COK 8410 Butorphanol Base 100

Example 20

Capsule Composition of Extended Release Butorphanol Ingredients Quantity(mg)/Dose Sterotex NF 320 Methocel K 15M 60 Aerosil COK 84 10Butorphanol Tartrate 300

Example 21

Capsule Composition of Extended Release Butorphanol Tartrate IngredientsQuantity (mg)/Dose Cithrol GMS 320 Methocel K 100M 55 Aerosil COK 84 15Butorphanol Tartrate 150

Example 22

Capsule Composition of Extended Release Butorphanol Tartrate IngredientsQuantity (mg)/Dose Sterotex ® NF 100 Fractionated coconut oil 70 Beeswax100 Methocel ® K 15M 81 Aerosil ® COK 84 4 Butorphanol Tartrate 200

Example 23

Capsule Composition of Extended Release Butorphanol Tartrate IngredientsQuantity (mg)/Dose Glyceryl behenate 135 Fractionated coconut oil 50Methocel ® K 15M 60 Aerosil ® COK 84 3 Butorphanol Tartrate 50

Example 24

Tablet Composition of Extended Release Butorphanol Tartrate IngredientsQuantity (mg)/Dose Lactose (spray dried) 230 Eudragit ™ RS PM 60Purified water q.s.* Stearyl Alcohol 90 Talc 8 Magnesium Stearate 4Butorphanol Tartrate 300 *Remains in product as residual moisture only.

In Example 24, the required quantities of Butorphanol Tartrate,spray-dried lactose, and Eudragit® RS PM are transferred into anappropriate-size mixer, and mixed for approximately 5 minutes. While thepowders are mixing, the mixture is granulated with enough water toproduce a moist granular mass. The granules are then dried in a fluidbed dryer at 60° C., and then passed through an 8-mesh screen.Thereafter, the granules are re-dried and pushed through a 12-meshscreen. The required quantity of stearyl alcohol is melted atapproximately 60 to 70° C., and while the granules are mixing, themelted stearyl alcohol is added. The warm granules are returned to themixer. The coated granules are removed from the mixer and allowed tocool. The granules are then passed through a 12-mesh screen. Thegranulate is then lubricated by mixing the required quantity of talc andmagnesium stearate in a suitable blender. Tablets are compressed on asuitable tableting machine.

In some embodiments, oral immediate release compressed tablets ofbutorphanol can be formulated using conventional wet granulationprocedures and equipment.

Example 25

Immediate Release Tablet Composition of Butorphanol Tartrate IngredientsQty./Unit 1. Butorphanol Tartrate 100 mg 2. Polyvinylpyrrolidine 7.5 mg3. Lactose 30 mg 4. Alcohol SD3A-2 proof 3 mL mg 5. Stearic acid 5 mg 6.Talc 7.5 mg 7. Cornstarch 20 mg

Example 26

Immediate Release Tablet Composition of Butorphanol Tartrate IngredientsQty./Unit 1. Butorphanol Tartrate 50 mg 2. Polyvinylpyrrolidine 7.5 mg3. Lactose 30 mg 4. Alcohol SD3A-2 proof 3 mL mg 5. Stearic acid 5 mg 6.Talc 7.5 mg 7. Cornstarch 20 mg

Example 27

Immediate Release Tablet Composition of Butorphanol Tartrate IngredientsQty./Unit 1. Butorphanol Tartrate 75 mg 2. Polyvinylpyrrolidine 7.5 mg3. Lactose 30 mg 4. Alcohol SD3A-2 proof 3 mL mg 5. Stearic acid 5 mg 6.Talc 7.5 mg 7. Cornstarch 20 mg

In Example 25 to 27, blend 1, 2 and 3 together; pass through a 40-meshscreen. Add 4 slowly and knead well. Screen wet mass through a 4-meshscreen. Dry the granulation at 50° C. overnight. Screen the driedgranulation through a 20-mesh screen. Bolt 5, 6 and 7 through a 60-meshscreen prior to mixing by tumbling with granulation. Compress using aconcave punch.

In some embodiments, oral immediate release compressed tablets ofbutorphanol can be formulated using conventional dry granulationprocedures and equipment.

Example 28

Tablet Composition of Butorphanol Tartrate Ingredients Qty./Unit 1Butorphanol Tartrate 20 mg 2 Lactose (granular, 12-mesh) 25 mg 3 Starch20 mg 4 Talc 20 mg 5 Magnesium Stearate 0.3 mg 

In Example 28, mix ingredients 1 to 5 thoroughly. Compress into slugs.Grind and screen to 14- to 16-mesh granules. Recompress into tabletsusing a concave punch.

In some embodiments, oral sustained release compressed tablets ofbutorphanol can be formulated using conventional fluid-bed granulationprocedures and equipment.

Example 29

Tablet Composition of Butorphanol Tartrate Ingredients Qty./Unit 1.Butorphanol Tartrate 50 mg 2. HPMC 2208, USP 150 mg 3. Carnauba wax 30mg 4. HPMC 2910, USP 15 mg 5. Magnesium Stearate 2 mg 6. Stearic acid 8mg 7. Talc 3 mg

In Example 29, place the ingredients 1, 2 and 3 in the granulator andmix for 15 minutes. Dissolve ingredient 4 in water (mix in how water,then cool down) and spay into the fluidized mixture. Dry toapproximately 5% moisture. Sequentially add ingredient 5, 6 and 7, withmixing steps between each addition. Compress using capsule shapedtooling.

In some embodiments, oral butorphanol for duodenal delivery, jejunaldelivery, ileal delivery, ileo-colonic delivery or colonic deliveryformulated as modified release dosage forms that provide: (i) rapidrelease of butorphanol from the dosage form in the appropriate GIenvironment; or (ii) extended or sustained release of butorphanol fromthe dosage form in the appropriate gastrointestinal environment. In someembodiments, the appropriate environment is defined by the anatomiclocation within the GI tract, pH at the point of release, osmoticpressure in the dosage form, osmotic pressure in the GI lumen at thepoint of release, level of hydration and/or the time after ingestion.

In some embodiments, an (otherwise) immediate release or a controlledrelease tablet dosage form may be overcoated with one or more polymersto provide butorphanol release in the appropriate gastrointestinalenvironment.

In some embodiments, oral modified release capsules of butorphanol forileal delivery, ileal release, ileo-colonic delivery, ileo-colonicrelease and/or colonic delivery and colonic release for rapid release inthe appropriate GI environment can be formulated using conventional wetgranulation technique.

Examples 30 to 31 are capsule formulations of oral modified releasecapsules of butorphanol for rapid release in the ileum or ileo-colonicregion. They are formulated using conventional wet granulationprocedures and equipment Example 30

Rapid Release Butorphanol Tartrate Capsules for Ileal or Ileo-colonicDelivery Ingredients Qty./Unit 1. Butorphanol Tartrate 4 mg 2.Polyvinylpyrrolidine 7.5 mg 3. Lactose 30 mg 4. Alcohol SD3A-2 proof 3mL mg 5. Stearic acid 5 mg 6. Talc 7.5 mg 7. Cornstarch 20 mg

Example 31

Rapid Release Butorphanol Tartrate Capsules for Ileal or Ileo-colonicDelivery Ingredients Qty./Unit 1. Butorphanol Tartrate 10 mg 2.Polyvinylpyrrolidine 7.5 mg 3. Lactose 30 mg 4. Alcohol SD3A-2 proof 3mL mg 5. Stearic acid 5 mg 6. Talc 7.5 mg 7. Cornstarch 20 mg

Example 32

Rapid Release Butorphanol Base Capsules for Ileal or Ileo-colonicDelivery Ingredients Qty./Unit 1. Butorphanol Base 5 mg 2.Polyvinylpyrrolidine 7.5 mg 3. Lactose 35 mg 4. Alcohol SD3A-2 proof 3mL mg 5. Stearic acid 5 mg 6. Talc 7.5 mg 7. Cornstarch 20 g

In Example 30 to 32, blend 1, 2 and 3 together; pass through a 40-meshscreen. Add 4 slowly and knead well. Screen wet mass through a 4-meshscreen. Dry the granulation at 50° C. overnight. Screen the driedgranulation through a 20-mesh screen. Bolt 5, 6 and 7 through a 60-meshscreen prior to mixing by tumbling with granulation. Encapsulate in anHPMC capsule.

Prepare a composition of aqueous Eudragit® L30D-55 dispersion to coat1.3 kg HPMC capsules: Eudragit L30D-55 1509 g (solids, 453 g), Triethylcitrate 91 g (solids 91 g), Tween 80 (33%) 20 g (solids 7 g) andDistilled Water 1130 g. Spray the dispersion onto the HPMC capsulesusing an Accela-Cota 10. The temperature of the capsule bed during thecoating process is maintained between 26 and 32° C. The mean amounts ofpolymer applied ranges from 5 mg/cm² to 20 mg/cm², preferably 5 mg/cm²to 10 mg/cm².

The in vitro performance of the capsules can be tested using methodsknow in the art and described herein. When the capsules are tested usingthe USP Paddle Method in 0.1N HCl (pH 1.2) for two hours, the capsuleswill remain intact and substantially non-releasing. Following a switchto phosphate buffer pH 6.8, the capsule dissolution is rapid andcomplete.

Examples 33 to 35 are capsule formulations of oral modified releasecapsules of butorphanol for rapid release in the ileo-colonic or colonicregion. They are formulated using conventional wet granulationprocedures and equipment

Example 33

Rapid Release Butorphanol Tartrate Capsules for Ileo-colonic or ColonicDelivery Ingredients Qty./Unit 1. Butorphanol Tartrate 2 mg 2.Polyvinylpyrrolidine 7.5 mg 3. Lactose 30 mg 4. Alcohol SD3A-2 proof 3mL mg 5. Stearic acid 5 mg 6. Talc 7.5 mg 7. Cornstarch 20 mg

Example 34

Rapid Release Butorphanol Tartrate Capsules for Ileo-colonic or ColonicDelivery Ingredients Qty./Unit 1. Butorphanol Tartrate 10 mg 2.Polyvinylpyrrolidine 7.5 mg 3. Lactose 30 mg 4. Alcohol SD3A-2 proof 3mL mg 5. Stearic acid 5 mg 6. Talc 7.5 mg 7. Cornstarch 20 mg

Example 35

Rapid Release Butorphanol Tartrate Capsules for Ileo-colonic or ColonicDelivery Ingredients Qty./Unit 1. Butorphanol Tartrate 6 mg 2.Polyvinylpyrrolidine 7.5 mg 3. Lactose 30 mg 4. Alcohol SD3A-2 proof 3mL mg 5. Stearic acid 5 mg 6. Talc 7.5 mg 7. Cornstarch 20 g

In Example 33 to 35, blend 1, 2 and 3 together; pass through a 40-meshscreen. Add 4 slowly and knead well. Screen wet mass through a 4-meshscreen. Dry the granulation at 50° C. overnight. Screen the driedgranulation through a 20-mesh screen. Bolt 5, 6 and 7 through a 60-meshscreen prior to mixing by tumbling with granulation. Encapsulate in anHPMC capsule.

Prepare a composition of aqueous Eudragit® FS30D dispersion to coat 1.3kg HPMC capsules: Eudragit FS30D 1207 g (solids, 362 g), Triethylcitrate 18 g (solids 18 g), Glyceryl monostearate 11 g (solids 11 g),Tween 80 (33%) 13 g (solids 4 g) and Distilled Water 728 g. Spray thedispersion onto the HPMC capsules using an Accela-Cota 10. Thetemperature of the capsule bed during the coating process is maintainedbetween 26 and 32° C. The mean amounts of polymer applied ranges from 5mg/cm² to 20 mg/cm², preferably 6 mg/cm² to 10 mg/cm².

The in vitro performance of the capsules can be tested using methodsknow in the art and described herein. When the capsules are tested usingthe USP Paddle Method in 0.1N HCl (pH 1.2) for two hours, followed by aswitch to phosphate buffer pH 6.8 for one to two hours and then again, aswitch to phosphate buffer pH 7.4, the capsules will remain intact andsubstantially non-releasing at pH 1.2 and pH 6.8 and will provide rapidand complete dissolution upon switch to pH 7.4.

In some embodiments, oral modified release capsules of butorphanol forileal release, ileo-colonic release and/or colonic release can beformulated using conventional dry granulation procedures and equipment.

Example 36 is a capsule formulation of oral modified release butorphanolfor rapid release in the ileo-colonic or colonic region. It isformulated using conventional dry granulation procedures and equipment.

Example 36

Rapid Release Butorphanol Tartrate Capsules for Ileo-colonic or ColonicDelivery Ingredients Qty./Unit 1 Butorphanol Tartrate 5 mg 2 Lactose(granular, 12-mesh) 25 mg 3 Starch 20 mg 4 Talc 20 mg 5 MagnesiumStearate 0.3 mg

In Example 36, mix ingredients 1 to 5 thoroughly. (Optionally, compressinto slugs and then grind and screen to 14- to 16-mesh granules). Fillinto HPMC capsules to provide the desired dose.

Prepare a composition of aqueous Eudragit® FS30D dispersion to coat 1.3kg HPMC capsules: Eudragit FS30D 1207 g (solids, 362 g), Triethylcitrate 18 g (solids 18 g), Glyceryl monostearate 11 g (solids 11 g),Tween 80 (33%) 13 g (solids 4 g) and Distilled Water 728 g. Spray thedispersion onto the HPMC capsules using an Accela-Cota 10. Thetemperature of the capsule bed during the coating process is maintainedbetween 26 and 32° C. The mean amounts of polymer applied ranges from 5mg/cm² to 20 mg/cm², preferably 6 mg/cm² to 10 mg/cm².

The in vitro performance of the capsules can be tested using methodsknow in the art and described herein. When the capsules are tested usingthe USP Paddle Method in 0.1N HCl (pH 1.2) for two hours, followed by aswitch to phosphate buffer pH 6.8 for one to two hours and then again, aswitch to phosphate buffer pH 7.4, the capsules will remain intact andsubstantially non-releasing at pH 1.2 and pH 6.8 and provide rapid andcomplete dissolution at pH 7.4.

In some embodiments, oral modified release tablets or capsule ofbutorphanol for ileal release, ileo-colonic release and/or colonicrelease can be formulated using conventional fluid-bed granulationprocedures and equipment.

Example 37 is a capsule (or optionally tablet) formulation of oralbutorphanol for ileo-colonic and colonic delivery.

Example 37

Modified Release Butorphanol Tartrate Capsules for Ileo-colonic orColonic Delivery Ingredients Qty./Unit 1. Butorphanol Tartrate 12 mg 2.HPMC 2208, USP 150 mg 3. Carnauba wax 30 mg 4. HPMC 2910, USP 15 mg 5.Magnesium Stearate 2 mg 6. Stearic acid 8 mg 7. Talc 3 mg

In Example 37, place the ingredients 1, 2 and 3 in the granulator andmix for 15 minutes. Dissolve ingredient 4 in water (mix in how water,then cool down) and spray into the fluidized mixture. Dry toapproximately 5% moisture. Sequentially add ingredient 5, 6 and 7, withmixing steps between each addition. Encapsulate the dosage form in HPMCor other suitable capsules or compress into a tablet.

For the capsule formulation, prepare a composition of aqueous Eudragit®FS30D dispersion to coat 1.3 kg HPMC capsules: Eudragit FS30D 1207 g(solids, 362 g), Triethyl citrate 18 g (solids 18 g), Glycerylmonostearate 11 g (solids 11 g), Tween 80 (33%) 13 g (solids 4 g) andDistilled Water 728 g. Spray the dispersion onto the HPMC capsules usingan Accela-Cota 10. The temperature of the capsule bed during the coatingprocess is maintained between 26 and 32° C. The mean amounts of polymerapplied ranges from 5 mg/cm² to 20 mg/cm², preferably 6 mg/cm² to 10mg/cm².

For the tablet formulation, the composition of aqueous Eudragit® FS30Ddispersion described above may be applied with a typical coatingthicknesses of 10 to 30 mg polymer per cm² of tablet surface,preferably, 10 to 18 mg polymer per cm² capsule surface.

The in vitro performance of the dosage form can be tested using methodsknow in the art and described herein. When the capsules are tested usingthe USP Paddle Method in 0.1N HCl (pH 1.2) for two hours, followed by aswitch to phosphate buffer pH 6.8 for one to two hours and then again, aswitch to phosphate buffer pH 7.4, the capsules will remain intact andsubstantially non-releasing at pH 1.2 and pH 6.8 and provide substantialrelease at pH 7.4.

In some embodiments, oral modified release capsule of butorphanol forileo-colonic and colonic delivery in sustained release form can be made,as shown in Example 9 to 21.

Example 38 to 51 may be prepared as follows: (i) Dispense the specifiedhydrophobic controlled release material (e.g., hydrogenated Type Ivegetable oil, hydrogenated Type II vegetable oil, polyoxyethylenestearates, polyoxyethylene distearates, glycerol monostearate, poorlywater soluble, or high melting point waxes) into a mixer; (ii) Heatuntil fully melted; (iii) dispense the hydroxypropyl methyl cellulose(HPMC) into the mixer; (iv) Mix until dispersed; (v) Dispense theAerosil into the same vessel; (vi) Mix until dispersed; (vii) Dispensethe butorphanol into the same vessel; (viii) Stir thoroughly with a highshear mixer; (ix) Transfer the mix into a liquid filling machine; (x)Fill into hard gelatin (or HPMC) capsule; (xi) Optionally, transfer thecapsules to a banding machine and band the capsules. Optionally, curethe capsules by setting them at room temperature for a period of 1 to 7days.

For Example 38 to 51, prepare a composition of aqueous Eudragit® FS30Ddispersion to coat 1.3 kg HPMC capsules: Eudragit FS30D 1207 g (solids,362 g), Triethyl citrate 18 g (solids 18 g), Glyceryl monostearate 11 g(solids 11 g), Tween 80 (33%) 13 g (solids 4 g) and Distilled Water 728g. Spray the dispersion onto the HPMC capsules using an Accela-Cota 10.The temperature of the capsule bed during the coating process ismaintained between 26 and 32° C. The mean amounts of polymer appliedranges from 5 mg/cm² to 20 mg/cm², preferably 6 mg/cm² to 15 mg/cm².

The in vitro performance of the dosage form can be tested using methodsknow in the art and described herein. When the capsules are tested usingthe USP Paddle Method in 0.1N HCl (pH 1.2) for two hours, followed by aswitch to phosphate buffer pH 6.8 for one to two hours and then again, aswitch to phosphate buffer pH 7.4, the capsules will remain intact andsubstantially non-releasing at pH 1.2 and pH 6.8, and they will releasethe butorphanol at pH 7.4 over a prolonged period (e.g., over 12 to 48hours).

Example 38

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Sterotex ® NF 200Fractionated coconut oil 70 Methocel ® K 15M 81 Aerosil ® COK 84 4Butorphanol Tartrate 20

Example 39

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Beeswax 200 HPMC, K15M 80Aerosil COK 84 8 Butorphanol Tartrate 10

Example 40

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Sterotex NF 150 HPMC,K15M 75 Coconut oil 75 Aerosil COK 84 5 Butorphanol Tartrate 12

Example 41

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Cithrol GMS 275 HPMC,K100M 40 Aerosil COK 84 10 Butorphanol Tartrate 20

Example 42

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Hydrokote 112 250 HPMC,K15M 60 Aerosil COK 84 10 Butorphanol Tartrate 5

Example 43

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Beeswax 200 HPMC,Pharmacoat 606 62.5 Aerosil COK 84 7.5 Butorphanol Tartrate 25

Example 44

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Gelucire 50/02 190Methocel K 100M 35 Aerosil COK 84 10 Butorphanol Tartrate 10

Example 45

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Cetyl alcohol 280Methocel K 100M 50 Aerosil COK 84 10 Butorphanol Tartrate 40

Example 46

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Sterotex NF 320 MethocelK 15M 60 Aerosil COK 84 10 Butorphanol Tartrate 15

Example 47

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Cithrol GMS 320 MethocelK 100M 55 Aerosil COK 84 15 Butorphanol Tartrate 15

Example 48

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Sterotex ® NF 100Fractionated coconut oil 70 Beeswax 100 Methocel ® K 15M 81 Aerosil ®COK 84 4 Butorphanol Tartrate 30

Example 49

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Cetyl alcohol 270Methocel K 100M 50 Aerosil COK 84 10 Butorphanol Tartrate 40

Example 50

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Sterotex NF 293 MethocelK 15M 45 Aerosil COK 84 10 Butorphanol Tartrate 10

Example 51

Modified Release Butorphanol Tartrate Capsules for Slow Ileo-colonic orColonic Release Ingredients Quantity (mg)/Dose Cithrol GMS 325 MethocelK 100M 55 Aerosil COK 84 15 Butorphanol Tartrate 20

Examples 52 and 53 are oral modified release tablets of butorphanol forileo-colonic and colonic delivery in sustained release.

The core tablet of butorphanol is prepared using the composition shownin the Tables for Examples 52 and 53 using the following procedure (i)Mix 1, 2, (and 3), and 5 and pass through #20 mesh; (ii) Dissolve 4 in7; (iii) Granulate the powder from (i) using a fluid bed granulator andthen dry; (iv) Pass the dry granules through #20 mesh; (v) Mix thegranules with 6; (vi) Compress to tablet using plain/plain tooling.

Prepare a coating solution comprising: (a) Ethylcellulose (EthocelPR100), 9.0 to 15 mg per tablet; (b) Polyvinylpyrrolidone (Kollidon90F), 3.0 to 7.0 mg per tablet; (c) Dibutyl Sebacate, 2.0 to 4.0 mg pertablet; (d) Denatured Alcohol 150 to 300 mg per tablet (evaporatesduring process). Spray coating solution using coating pan until desiredin vitro release is achieved as described herein. Adjust coatingsolution composition or coating weight/thickness as required. Thecoating weight is usually approximately 5 to 40% w/w.

For the initial trial, prepare one coating comprising: (a)Ethylcellulose (Ethocel PR100), 9.2 mg per tablet; (b)Polyvinylpyrrolidone (Kollidon 90F), 4.15 mg per tablet; (c) DibutylSebacate, 2.70 mg per tablet; (d) Denatured Alcohol 170 mg per tablet(evaporates during process). Prepare another coating comprising: (a)Ethylcellulose (Ethocel PR100), 14.15 mg per tablet; (b)Polyvinylpyrrolidone (Kollidon 90F), 5.1 mg per tablet; (c) DibutylSebacate, 3.85 mg per tablet; (d) Denatured Alcohol 245 mg per tablet(evaporates during process).

Example 52

Modified Release Butorphanol Tartrate Tablets for Slow Ileo-colonic orColonic Release Quantity Ingredients (mg) 1. Butorphanol Tartrate 40.002. Microcrystalline 90.00 Cellulose 3. HPMC (low viscosity 46.00 grade)4. Polyvinyl Alcohol 2.00 5. Colloidal Silicon 1.00 Dioxide 6. SodiumStearyl 1.00 Fumarate 7. Purified Water * As needed to form granules *Evaporated during process

Example 53

Modified Release Butorphanol Tartrate Tablets for Slow Ileo-colonic orColonic Release Quantity Ingredients (mg) 1. Butorphanol Tartrate 10.002. Microcrystalline 90.00 Cellulose 3. HPMC (low viscosity — grade) 4.Polyvinyl Alcohol 2.00 5. Colloidal Silicon 1.00 Dioxide 6. SodiumStearyl 1.00 Fumarate 7. Purified Water * 41.60 (to form granules) *Evaporated during process

Alternatively, Examples 52 and 53 may be coated with a suitable amountof Eudragit® S 100, or Eudragit® S 12.5, or Eudragit® FS 30D

Example 54

Example 54 provides a method for manually sealing the overlapping regionof the HPMC capsule body and cap using a process called banding. Thebanding solution is prepared as follows: (i) prepare the bandingsolution with 18 g of 4.5 cps HPMC along with 33 g of water and heatedto 80° C. in a beaker; (ii) stir the mixture until the HPMC is welldispersed in the water; (iii) to completely solubilize the HPMC, add 50mL of absolute alcohol and sonicate for 10 minutes; (iv) seal capsulesusing equipment such as the Lab band sealing machine (LBS 100) or theQualicaps® Lab-Top Capsule Band-Sealer (S-1); (v) apply banding solutionuniformly to the external edge of the gap of the capsule to be sealed toform a liquid ring around the circumference of the capsule and removeexcess sealing liquid from the exterior of the capsule; (vi) dry thecapsules by applying thermal energy, such as hot air and a controlledtemperature oven. For larger scale banding, automated equipment such asthe Qualicaps S-40 or S-100 capsule band-sealing machine or theHermetica® is a capsule banding machine may be used to seal filled,two-piece capsules with a single or double band of substances such asgelatin or hypromellose at the joined portion of the cap and body.

Example 55

Example 55 provides an alternative method of coating small batches ofcapsules to provide ileo-colonic or colonic deliver of the oralbutorphanol dosage form for rapid release or slow release (depending onthe dosage form used). This method can be used in place of otherdescribed enteric coating methods. The method can be readily modified bythose skilled in the art to coat tablet dosage forms. In this example,coating is carried out using 45% suspension of Eudragit® FS30D. Coatingsolution is prepared by homogenizing talc and triethyl citrate in waterfor 10 minutes. This suspension is poured into Eudragit FS 30 Ddispersion under stirring. This spray suspension is transferred through0.5 mm sieve. Coating suspension is spread by spray gun on a movingcapsule bed. The process is carried out in conventional coating pan (seeTable below). The coating solution may be further modified to achievetargeted GI delivery or release in or distal to the duodenum, jejunum,ileum, ileo-cecal junction, ileo-colonic region or colon, using methodsknown in the art and those described herein.

Composition of Coating Solution Ingredients Enteric coating Eudragit FS30 D 150 g Talc 22.5 g Triethyl citrate 2.5 g Water 175 g

The coating process parameters like the coating pan, baffles, inlet airtemperature, product temperature, exhaust and spray air pressure areshown in Table below.

Coating Process Parameters Coating pan 12 inch Baffles Present Siliconetube od/id 2 mm Inlet air temperature 40° C. Product Temperature 30° C.Exhaust ON Blower ON Spray air pressure 2 bar

Example 56

Example 56 provides an alternative method of coating small batches ofcapsules to provide ileo-colonic or colonic delivery of the oralbutorphanol dosage form for rapid release or slow release (depending onthe dosage form used). This method can be used in place of otherdescribed enteric coating methods. The method can be readily modified bythose skilled in the art to coat tablet dosage forms. The coatingsolution may be further modified to achieve targeted GI delivery orrelease in or distal to the duodenum, jejunum, ileum, ileo-cecaljunction, ileo-colonic region or colon, using methods known in the artand those described herein. An initial coating solution is provided inthe Table below. This can be modified further to achieve the desireddelivery profile:

S. No. Ingredients % w/w 1 Eudragit S 100 6.1 2 Triethyl citrate 0.9 3Talc 3.0 4 Isopropyl alcohol 85.0 5 Water 5.0

The procedure for preparation of the above coating solution is: (a)dissolve Eudragit in 70% of total IPA and 100% of water; (b) homogenizetalc and triethyl citrate in 30% of remaining IPA; (c) add talc andtriethyl citrate dispersion to Eudragit solution and stir gently. Applythe coat by dip coating using the ProCoater® (Torpac, N.J.), with themethod recommended by the manufacturer or preferably described bydescribed by Dodds and Podczeck (Tablets & Capsules, January 2008, CSCPublishing Inc). Once dry, check weight gain. Additional coating may beapplied to provide further weight gain. Batches with polymer targetweight gains of about 10 mg/cm² to about 20 mg/cm² are prepared (forexample, 10 mg/cm² or 15 mg/cm² and 20 mg/cm²). The approximate surfacearea of Capsule Size 00, 0, 1 and 2 are 6.16 cm², 5.07 cm², 4.06 cm²,and 3.43 cm², respectively (see Jones, Tablets & Capsules, January 2009and April 2009, CSC Publishing Inc). This provides a target weight gainrange shown below:

Capsule Surface Total Capsule Weight Gain Size Area 10 mg/cm² 15 mg/cm²20 mg/cm² 00 6.16 cm² 60 mg 90 mg 120 mg 0 5.07 cm² 50 mg 75 mg 100 mg 14.06 cm² 40 mg 60 mg  80 mg 2 3.43 cm² 35 mg 50 mg  70 mg

To determine if the desired target delivery or release has beenachieved, a disintegration tester is used (e.g. manually with theERWEKA® ZT 120, ZT 120, ZT 220, or ZT 320, or using the automated ZT850). Alternatively, an orbital shaker or a beaker with an agitator (ormagnetic stirrer at moderate or high speed) is used, first in 0.1N HClfor two hours, then with a change in media to water at pH>7 (or othersuitable pH). The capsules shell remains intact in 0.1 N HCL (pH 1.2)for two hours and disintegrates or ruptures at the desired pH (e.g., pH7) usually after 5 to 90 minutes (the higher the weight gain, the longerthey stay intact at pH 7). For modified release dosage forms intended toprovide targeted GI delivery (e.g., ileo-colonic or colonic delivery)for subsequent slow or sustained release, the capsule shell willrupture, disintegrate, or dissolve but the contents may remain intact(depending on the dosage form used).

A more specific and reliable method to determine coating integrity andattainment of target GI delivery (which does not rely on visualinspection of capsules) for both modified release forms which rapidlyrelease drug and those which slowly release (sustained release) drug inthe target GI environment is the use of a dissolution methods where thedrug release is quantified. When such the capsules are tested using theUSP Paddle Method in 0.1N HCl (pH 1.2) for 2 hours at 37° C., thecapsules (or tablets) remain intact and substantially non-releasing.Following a switch to the USP Basket or Paddle Method at 100 rpm in 900mL distilled water (time=0 hour begins here) at 37° C. at the target pH,the dosage form begins to provide rapid or slow release of the drugusually after 5 to 90 minutes.

The optimal coating solution composition, weight gain and processparameters to achieve the desired target delivery or release is achievedby simultaneously testing the coated dosage form dosage form at variouspH using the USP Paddle Method in 0.1N HCl (pH 1.2) for 2 hours at 37°C., followed by a switch to the USP Basket or Paddle Method at 100 rpmin 900 mL distilled water (time=0 hour begins here) at 37° C. at thetarget pH (e.g., pH 6.5, pH 6.8, pH 7.0, pH 7.5). For modified releasedosage forms intended to provide targeted GI delivery for rapid releaseof butorphanol, less than 10% of drug should be released at pH 1.2.

Various alternative small and large scale methods of organic and aqueouscoating of tablets and capsules have been described or referencedherein, or are known those skilled in the art. Enteric coatings may alsobe applied over tablet and capsule osmotic delivery dosage forms of oralbutorphanol, including push pull osmotic pumps, monolithic osmoticdelivery systems and controlled porosity osmotic pumps to providetargeted delivery in the GI tract.

Example 57

A matrix tablet formulation of oral modified release butorphanol wasprepared using the method described here: (i) The Polyox and MCC werepassed through a 44# sieve and then weighed; (ii) Butorphanol Tartratewas weighed and milled in mortar-pestle to make fine powder; (iii) Themixture of step (i) was mixed with step (ii) to provide a homogeneousmixture. Uniform mixture was achieved through sieving several times andmixing geometrically; (iv) The lubricants were added and passed through25 # sieve in above mixture by sieving them with step (iii); (v) Themixture was well mixed and sieved through a 25# sieve twice andhomogenized in a polybag; (vi) tablets were compressed using a standardconcave 9 mm punch on single punch compression machine.

Modified Release Butorphanol Matrix Tablets Drug Layer mg/Tablet % w/w 1Butorphanol Tartrate 10.0 5.0 2 Polyox WSR 301 100.0 50.0 3 MCC 101 80.040.0 4 Talc 3.0 1.5 5 Mg. Stearate 3.0 1.5 6 SiO2 4.0 2

The tablet dissolution was evaluated in 250 mL of pH 1.2 for 2 hours,followed by a switch to pH 6.8 phosphate buffer using the USP paddlemethod at 50 rpm, and in 250 mL of pH 6.8 phosphate buffer using the USPpaddle method at 100 rpm and. See Table below.

Modified Release Butorphanol Matrix Tablet Dissolution Dissolution Rate(% w/w) Time pH 1.2 (2 hrs), then pH 6.8 Dissolution Rate (% w/w) (hr)50 RPM pH 6.8, 100 RPM 1 11.10 5.78 2 17.76 10.58 4 31.83 24.16 6 46.5641.16 8 57.92 54.50 10 65.88 67.95 14 87.26 82.10 17 99.03 97.01 21101.44 106.26 24 101.80

Example 58

A matrix tablet formulation of oral modified release butorphanol wasprepared using the method described here: (i) The Polyox, HPMC K100M CRand MCC were passed through a 44 # sieve and then weighed; (ii)Butorphanol Tartrate was weighed and passed through a 25# sieve; (iii)The mixture of step (i) was mixed with step (ii) to provide ahomogeneous mixture. Uniform mixture was achieved through sievingseveral times and mixing geometrically; (iv) The lubricants were addedand passed through 100 # sieve in above mixture by sieving them withstep (iii); (v) The mixture was well mixed and sieved through a 25#sieve twice and homogenized in a polybag; (vi) tablets were compressedusing a standard concave 9 mm punch on single punch compression machine.

Modified Release Butorphanol Matrix Tablets Drug Layer mg/Tablet % w/w 1Butorphanol Tartrate 10.0 5.0 2 Polyox WSR 301 50.0 25.0 3 HPMC K100M CR50.0 25.0 4 MCC 101 80.0 40.0 5 Talc 3.0 1.5 6 Mg. Stearate 3.0 1.5 7SiO2 4.0 2

The tablet dissolution was evaluated in 250 mL of pH 1.2 for 2 hours,followed by a switch to pH 6.8 phosphate buffer using the USP paddlemethod at 50 rpm, and in 250 mL of pH 6.8 phosphate buffer using the USPpaddle method at 100 rpm and. See Table below.

Modified Release Butorphanol Matrix Tablet Dissolution Dissolution Rate(% w/w) Time pH 1.2 (2 hrs), then pH 6.8 (hr) 50 RPM 1 7.55 2 15.50 420.24 6 36.17 8 47.89 10 54.81 14 76.02 17 82.51 21 88.99 24 92.66

Example 59

A controlled porosity osmotic pump (CPOP) dosage form of oralbutorphanol was prepared using the method described here.

Core Tablet: (i) Butorphanol tartrate was mixed with lactose and sodiumchloride after passing through 40# sieve; (ii) The mixture of step (1)was added to PVP K 30 solution in IPA; (iii) The mass was well mixed toachieve a homogeneous mixture; (iv) The mass dried in a dryer at 50° C.for 10 minutes; (v) The mass was passed through a #18 sieve once forgranulation; (vi) The granules were further dried; (vii) Magnesiumstearate and talc were then added and mixed; (viii) The tablets werecompress using a standard concave 9 mm punch on single punch compressionmachine.

Coating Solution: (i) Cellulose acetate was dissolved in acetone; (ii)D-sorbitol was dissolved in water half quantity; (iii) PEG was dissolvedin rest of the one fourth of water; (iv) Step (ii) was mixed with step(1) with high stirring; (v) Mix step (iii) with the mixture of step (i)and step ii); (vi) Stir to homogenize the solution; (vii) Dip the tubeof the coating solution dispenser into the product of step (vi).

Modified Release Osmotic Dosage Form Core Tablet Drug Layer mg/Tablet %w/w 1 Butorphanol Tartrate 10.0 4.3 2 Sodium Chloride 100.0 43.5 3Lactose 100.0 43.5 4 PVP K 30 in IPA 3 ml 12.0 5.2 5 Mg. Stearate 3.01.3 6 Talc 3.0 1.3 7 Aerosil 200 2.0 0.87

Modified Release Osmotic Dosage Form Coating Solution Coating Formulamg/Tablet % w/w 1 Cellulose Acetate 22.95 2.39 2 D-Sorbitol 4.05 0.42 3PEG-400 4.05 0.42 4 Acetone 855.00 88.97 5 Water 75.00 7.80

Modified Release Osmotic Dosage Form Coating Process Parameters CoatingParameters Solvent Acetone:Water (90:10) Solids content (% w/w) 4%(3.23%) Weight gain (%) 15% Target/13.71 Achieved Inlet air temperature(° C.) 50-55° C. (Set) 49°Actual Out let air temperature (° C.) 45-50°C. (Set) 40° Actual Inlet air CFM 32 Outlet air CFM 43 Tablet surfacebed temp (° C.) 40-42° C. Pre-warm tablet bed (° C.) 41-43° C. Load 175gm Atomizing air pressure (kg/cm²) 3.0 kg/cm² Gun-to-bed distance(inches) Three to Four inch Spray rate (g/min) 4.5 to 5.5 g\min Baffles 6 Pan speed (rpm) 3.0 RPM Peristaltic Pump RPM 10 RPM Fluid nozzle (mm) 1.5 Spray equipment Solace Spray pan size 12″

The tablet dissolution was evaluated in 250 mL of pH 6.8 phosphatebuffer using the USP paddle method at 50 rpm after application ofcoating in the following w/w % amounts: (i) 5.7%; (ii) 9.6%; and(13.7%). See Table below.

Modified Release Osmotic Dosage Form Dissolution Time Dissolution Rate(i) Dissolution Rate (ii) Dissolution Rate (iii) (hr) (% w/w) (% w/w) (%w/w) 1 0.00 0.00 0.00 2 0.65 0.40 0.00 4 19.72 7.24 5.56 6 37.15 26.6217.55 8 58.42 38.84 23.50 10 61.62 43.42 34.41 14 79.19 58.66 40.42 1782.64 64.34 51.41 21 85.02 68.51 56.35 24 89.72 75.02 60.10

Example 59

Numerous robust matrix butorphanol tartrate tartrate formulations of theinvention suitable for 24 hour dosing (QD dosing) were prepared andtested in 500 mL of 0.1N HCl (at pH 1.2) at 37 C for 2 hours, followedby a switch to pH 6.8 phosphate buffer and also exclusively in pH 6.8buffer under the same conditions. They provided the followingdissolution release specifications: less than about 20% release at 1hour, between about 15% and about 55% release at 4 hours, between 35%and 75% release at 8 hours and greater than 70% release at 24 hours.Using methods described herein, the matrix tablets may be furtherovercoated to provide ileo-colonic release, which when tested in 0.1 NHCl (at pH 1.2) or at pH 5 for 2 hours, followed by a switch to pH 6.8phosphate buffer tested will provide the following dissolution releasespecifications: less than about 10% release at 2 hours, between about15% and about 55% release at 6 hours, between 35% and 75% release at 10hours and greater than 55% release at 24 hours.

Example 60

Numerous robust controlled porosity osmotic pump butorphanol tartratedosage forms of the invention suitable for 24 hour dosing (QD dosing)were prepared and tested in 500 mL of pH 6.8 phosphate buffer at 37 Cand in distilled water. They provided the following dissolution releasespecifications: less than about 20% at 3 hours, about 15% to 55% at 6hours, about 35% and 75% at 10 hours and greater than 60% at 24 hours.Using methods described herein, the matrix tablets may be furtherovercoated to provide ileo-colonic release, which when tested in 0.1 NHCl (at pH 1.2) or at pH 5 for 2 hours, followed by a switch to pH 6.8phosphate buffer tested will provide the following dissolution releasespecifications: less than about 10% release at 2 hours, less than about30% at 5 hours, about 15% to 60% at 8 hours, about 30% and 85% at 10hours and greater than 50% at 24 hours.

Example 61

A matrix tablet formulation of oral modified release butorphanol wasprepared using the method described here: (i) The Polyox, HPMC K100M CRand MCC were passed through a 44# sieve and then weighed; (ii)Butorphanol Tartrate was weighed and passed through a 25# sieve; (iii)The mixture of step (i) was mixed with step (ii) to provide ahomogeneous mixture. Uniform mixture was achieved through sievingseveral times and mixing geometrically; (iv) The lubricants were addedand passed through 100# sieve in above mixture by sieving them with step(iii); (v) The mixture was well mixed and sieved through a 25# sievetwice and homogenized in a polybag; (vi) tablets were compressed using astandard concave 9 mm punch on single punch compression machine.

Modified Release Butorphanol Matrix Tablets Drug Layer mg/Tablet % w/w 1Butorphanol Tartrate 5.0 5.0 2 Polyox WSR 301 50.0 25.0 3 HPMC K100M CR50.0 25.0 4 MCC 101 85.0 42.5 5 Talc 3.0 1.5 6 Mg. Stearate 3.0 1.5 7SiO2 4.0 2

The tablet dissolution was evaluated in 250 mL of pH 1.2 for 2 hours,followed by a switch to pH 6.8 phosphate buffer using the USP paddlemethod at 50 rpm, and in 250 mL of pH 6.8 phosphate buffer using the USPpaddle method at 100 rpm and. See Table below.

Modified Release Butorphanol Matrix Tablet Dissolution Dissolution Rate(% w/w) Time pH 1.2 (2 hrs), then pH 6.8 Range (hr) 50 RPM (% w/w) 1 9<20 2 15 4 29 15-55 6 37 8 48 35-75 10 52 24 52 >70

Example 62

A matrix tablet formulation of oral modified release butorphanol wasprepared using the method described previously.

Formula Excipient mg/tab % w/w Range 1 Range 2 Butorphanol tartrate 10.04.0 Microcrystalline cellulose 101 100.0 40.0 Hypromellose K100M 87.535.0 25%-45% 15%-55% Ethyl cellulose N7 25.0 10.0  5%-20%  0%-30% Talc1.25 0.5 Aerosil 200 1.25 0.5 Carbopol 71G 25.0 10.0 Total 250.0 100.0

The tablet dissolution was evaluated in 250 mL of pH 1.2 for 2 hours,followed by a switch to pH 6.8 phosphate buffer using the USP paddlemethod at 50 rpm. See Table below.

Time (hr) Avg Range 0 0 1 13 <20 2 20 4 30 15-55 6 36 8 42 35-75 24 74>70

A matrix tablet formulation of oral modified release butorphanol wasprepared using the method described previously.

Formula Excipient mg/tab % w/w Range 1 Range 2 Butorphanol tartrate 10.05.0 POLYOX WSR 301 50.0 25.0 15%-35% 10%-40% Hypromellose K4M 50.0 25.015%-35% 10%-40% Microcrystalline cellulose 79.625 39.8125 101 BTH EP0.375 0.1875 Talc 3.0 1.5 Magnesium Stearate 3.0 1.5 Silicone dioxide4.0 2.0 Total 200.0 100.0

The tablet dissolution was evaluated in 250 mL of pH 6.8 phosphatebuffer using the USP paddle method at 50 rpm. See Table below.

Time (hr) Avg. Range 1 5 <20 2 15 4 34 15-55 6 46 8 57 35-75 10 64 14 7517 82 21 86 24 86 >70

nnnnnnnnnnnn

Antinociceptive Effects of Oral Butorphanol

Radiant Heat Tail Flick Test

Background

The tail flick test was first described by D'Amour and Smith (1941), andremains essentially unchanged in application. (See generally D'Amour, F.E. and Smith, D. L., “A method for determining loss of pain sensation”,J. Pharmacol. Exp. Therap., 72:74-79 (1941); Dewey, D. L. and Harris, L.S., The Tail-flick test. In: S. Ehrenpreis and A. Neidle (Eds.), Methodsin Narcotic Research, Marcel Dekker, Inc., New York, 1975, pp. 101-109;and Dubner, R. and Ren, K., “Assessing transient and persistent pain inanimals” In: P. D. Wall and R. Melzack (Eds.), Textbook of Pain,Churchill Livingstone, London, 1999, pp. 359-369). Quite simply, thetail of a rat or mouse is exposed to radiant heat, and the latency towithdraw is determined. The basal heat intensity is set so that naïverats withdraw their tails within 2 to 3 sec. A cut-off latency of 10 sec(i.e., 3 to 4 times basal control value) is commonly employed to preventtissue damage. An alternative to using radiant heat is to dip the tailinto a water bath maintained at a fixed temperature, usually in themoderately noxious range of about 52° C. or 55° C. One advantage of awater bath is that the temperature is kept constant.

The tail-flick test is considered to be very robust in that weakanalgesic agents are not detected by this test. In contrast, it isconsidered highly selective. There is a high degree of correlationbetween drugs that are identified as antinociceptive in the tail-flicktest and clinically active analgesic agents. Importantly, agents thatare sedating and may produce a positive response in the writhing test orhot plate test do not show antinociceptive activity in the tail-flicktest. It is even possible to perform the tail-flick test in lightlyanesthetized animals.

Example 60 Aim

The aim of this study was to evaluate the analgesic effect of orallyadministered butorphanol following administration into different partsof the gastrointestinal tract in transiently ether anaesthetized rats,using the tail flick test of nociception. The primary measurements weremade using the tail flick test designed to detect effects of thetreatment(s) on nociception in rats.

Animals:

Wistar rats weighing 250±20 g were maintained on standard laboratorydiet and having free access to tap water ad lib were employed in thepresent study. They were housed in the animal house and were exposed to12 hr cycle of light and dark. The experiments were conducted in asemi-sound proof laboratory. Care of the animals was in accordance withguidelines for experimentation on animals.

Experimental Design:

Three groups were employed in the present study with each groupcomprising of 8 animals. Each animal was subjected to transient etheranesthesia followed by a minor incision in the abdominal cavity throughwhich butorphanol 1 mg/kg was administered using a syringe into thestomach, ileum and colon. Tail flick test was performed 0, 30, 45 and 60minutes after administration of the butorphanol. Area under the curvewas calculated using a graph between % MPE and time. Area under thecurve was employed as a quantitative measure of the analgesic effect ofthe treatments.

Measurement of Effect:

Nociceptive threshold was measured with the tail flick test (D'Amour andSmith, 1941). The tail flick latency was considered as the time betweenexposure of the tail to radiant heat and tail withdrawal. Electricallyheated nichrome wire was used as a source of radiant heat in theanalgesiometer. The intensity of radiant heat was regulated in order toobtain a pretreatment latency between 2 and 4 sec in the animals. Acut-off latency time was fixed at 10 sec. Tail flick latency isexpressed as a percentage of the maximum possible effect (MPE):

${M\; P\;{E(\%)}} = {\frac{\left( {{{Post}\mspace{20mu}{treatment}\mspace{14mu}{latency}} - {{pre}\mspace{14mu}{treatment}\mspace{14mu}{latency}}} \right)}{\left( {{{Cut}\text{-}{off}\mspace{14mu}{time}} - {{pre}\mspace{14mu}{treatment}\mspace{14mu}{latency}}} \right)} \times 100}$

Data Analysis:

The anti-nociceptive effect following intragastric, intra-ileal andintra-colonic administration was assessed in terms of area under thecurve calculated from a graph having time (relative to dosing timepoint) on the x-axis and percent maximum possible effect (% MPE) on they-axis. The results were expressed as mean±standard error of means(S.E.M.). Statistical analysis for was done using one-way ANOVA,followed by Tukey's multiple range tests as post-hoc analysis. A valueof P<0.05 was considered to be statistically significant.

Results:

Intra-gastric, intra-ileal, and intra-colonic administration ofbutorphanol each caused a significant increase in the tail flick latencyin rats. However, intra-colonic administration of butorphanol produced asignificantly greater antinociceptive effect that intra-gastric orintra-ileal (see FIG. 13).

Hot Plate Test

Background

Heat is often used as a noxious stimulus in models of pain. Typically,the latency of the rat's response to the thermal stimulus is recorded asthe dependent variable. To determine whether a test compound hasanalgesic properties, the latency responses of treated and control ratsare evaluated. A significant increase in the latency to respond to thethermal stimulus after a treatment relative to a control treatment isinterpreted as an antinociceptive or analgesic response. The latency ofresponse will vary depending on the type of heat stimulus used. In thehot-plate assay, the rat is placed on a heated surface and the latencyfor the rat to respond to the stimulus, by licking its paw or jumping,is recorded.

Example 61 Aim

The aim of this study was to evaluate the analgesic effect of orallyadministered butorphanol following administration into different partsof the gastrointestinal tract in transiently ether anaesthetized rats,using the hot plate test of nociception The primary measurements weremade using the hot plate test designed to detect effects of thetreatment(s) on nociception in rats.

Animals:

Wistar rats weighing 250±20 g were maintained on standard laboratorydiet and having free access to tap water ad lib were employed in thepresent study. They were housed in the animal house and were exposed to12 hr cycle of light and dark. The experiments were conducted in asemi-sound proof laboratory. Care of the animals was in accordance withguidelines for experimentation on animals.

Experimental Design:

Three groups were employed in the present study with each groupcomprising of 8 animals. Each animal was subjected to transient etheranesthesia followed by a minor incision in the abdominal cavity throughwhich butorphanol 1 mg/kg was administered using a syringe into thestomach, ileum and colon. Hot plate latency was assessed at 0, 30, 45and 60 minutes after administration of the butorphanol. Area under thecurve was calculated using a graph between % MPE and time. Area underthe curve was employed as a quantitative measure of the analgesic effectof the treatments.

Measurement of Effect: Nociceptive threshold was measured with theEddy's hot plate test. The reaction time was considered as the timebetween placing of the rat on the Eddy's hot plate heated to atemperature of 52.5° C. and the reaction of the animal in the form of ajump or fore paw licking reflex. A cut-off latency time was fixed at 10sec. Reaction time is expressed as a percentage of the maximum possibleeffect (MPE):

${M\; P\;{E(\%)}} = {\frac{\left( {{Post}\mspace{20mu}{treatment}\mspace{14mu}{latency}\text{-}{pre}\mspace{14mu}{treatment}\mspace{14mu}{latency}} \right)}{\left( {{{Cut}\text{-}{off}\mspace{14mu}{time}} - {{pre}\mspace{14mu}{treatment}\mspace{14mu}{latency}}} \right)} \times 100}$

Data Analysis:

The anti-nociceptive effect following intragastric, intra-ileal andintra-colonic administration was assessed in terms of area under thecurve calculated from a graph having time (relative to dosing timepoint) on the x-axis and percent maximum possible effect (% MPE) on they-axis. The results were expressed as mean±standard error of means(S.E.M.). Statistical analysis for was done using one-way ANOVA,followed by Tukey's multiple range tests as post-hoc analysis. A valueof P<0.05 was considered to be statistically significant.

Results:

Intra-gastric, intra-ileal, and intra-colonic administration ofbutorphanol each caused a significant increase in the hot plate latencyin rats. However, intra-colonic administration of butorphanol produced asignificantly greater antinociceptive effect that intra-gastric orintra-ileal (see FIG. 14).

Chemotherapy Induced Peripheral Neuropathy Example 62 Aim

The aim of this study was to evaluate the effect of oral administrationof butorphanol in rats with vincristine induced painful neuropathy. Theprimary measurements were made mechanical and thermal allodynia designedto detect effects of the treatment(s) on neuropathic pain.

Animals:

Wistar rats weighing 250±20 g were maintained on standard laboratorydiet and having free access to tap water ad lib were employed in thepresent study. They were housed in the animal house and were exposed to12 hr cycle of light and dark. The experiments were conducted in asemi-sound proof laboratory. Care of the animals was in accordance withguidelines for experimentation on animals.

Experimental Design:

The vincristine model was adapted from Authier et al (1999). Rats wereinjected on five alternate days (day 4, 6, 8, 10 & 12) with vincristine(200 μg/kg i.p.) using an injection volume of 2 ml/kg. Thus, thecumulative dose of vincristine was computed to be 1 mg/kg. Tests tookplace three days after the last injection and continued over the nextthree weeks. Five groups were employed in the present study with eachgroup comprising of 8 animals: Group I: Vehicle control group 2 ml/kg,i.p.; Group II: Oral butorphanol 1 mg/kg; Group III: Oral butorphanol 3mg/kg; Group IV: Oral butorphanol 10 mg/kg; Group V: Oral butorphanol 30mg/kg.

Measurement of Effect

Assessment of Mechanical Allodynia

Mechano-allodynia was assessed using von Frey filaments. The filamentsare nylon monofilaments of different diameters that exert defined levelsof force to cause the hair to bend. Once a rat was calm, a series of vonFrey filaments with roughly exponential incremental target force (0.008,0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1, 1.4, 2, 4, 6, 8, 10, 15, 26, 60,100, 180, 300 g) were applied to the bottom of the right paw, behind thefront pads and lateral to the medial pads of the rat. The filament waspresented perpendicular to the rat paw and applied with enough force soas to cause a slight bend. It was held steadily against the paw for aperiod of 5 s. A response was considered positive if, within the 5-speriod, the rat withdrew from the stimulus or briskly withdrewimmediately after the filament was removed. A negative response was theone in which the rat did not withdraw within the given time. Testing wasinitiated using middle filament (2 g). A negative response required theuse of next filament with greater bending force. A positive responserequired the use of next filament with less bending force. Both hindpaws were tested for allodynia and the average of the two was recordedas data. Results were expressed in grams and determined before and 30and 60 min after the administration of the test drugs.

Assessment of Cold Allodynia

For the assessment of cold allodynia, which was stable for 3 weeks, therats were placed on a wire mesh covered with a plastic dome and wereallowed to habituate until the exploratory behavior diminished. Coldallodynia was measured as the number of foot withdrawal responses afterapplication of stimuli to the plantar surface of the paw. A drop ofacetone (10 μl) was gently applied to the heel of the animal with amicro-pipette. A brisk foot withdrawal response (shaking, tapping, orlicking) after the spread of acetone over the plantar region of the pawwas considered a sign of cold allodynia. Acetone was applied two times(once every 5 min) on the left paw, and the number of reactions(shaking, tapping, or licking) was counted during 30 sec. A cut-offnumber of reactions were fixed at 20 per trial (i.e. 40). The score wasexpressed as accumulated numbers of reactions over the trials anddetermined before and 30 and 60 min after administration of the testdrugs. Each individual test was expressed as a percentage of maximumpossible effect (% MPE):

${M\; P\;{E(\%)}} = {\frac{\left( {{{Post}\mspace{20mu}{treatment}\mspace{14mu}{frequency}} - {{pre}\mspace{14mu}{treatment}\mspace{14mu}{latency}}} \right)}{\left( {{{Cut}\text{-}{off}\mspace{14mu}{frequency}} - {{pre}\mspace{14mu}{treatment}\mspace{14mu}{latency}}} \right)} \times 100}$

The peak effect was seen at a time point 30 minutes after the drugadministration. MPE (%) at 30 min time point was employed as aquantitative measure of the analgesic effect of the test drugs.

Data Analysis:

The anti-nociceptive effect was plotted assessed having time (relativeto dosing time point) on the x-axis and percent maximum possible effect(% MPE) on the y-axis. The results were expressed as mean±standard errorof means (S.E.M.). Statistical analysis for was done using one-wayANOVA, followed by Tukey's multiple range tests as post-hoc analysis. Avalue of P<0.05 was considered to be statistically significant.

Results

Response to Mechanical Allodynia

Baseline mean mechanical withdrawal threshold in the vincristinetreatment induced neuropathic rat was observed to be 4.04±0.77 g. Allanimals included in the study had a mean threshold below five, thusconforming to the requirements of being considered neuropathic. Oraladministration of butorphanol demonstrated a dose dependent increase inthe mechanical withdrawal threshold that elicits pain in the neuropathicrats. Moreover, the effect of the butorphanol was dependent on the doseand the peak effect of drug was noted to be 30 min post-administration(FIG. 15).

Response to Cold Allodynia

Baseline of cold allodynia score was determined using the acetone droptest in the vincristine treatment induced neuropathic rats. Moreover,effect of the drug was dependent on the dose and the peak effect of drugwas noted to be 30 min post-administration. Furthermore, the oraladministration of butorphanol demonstrated a dose dependent decrease inthe cold allodynia score in the neuropathic rats (FIG. 16).

Conclusion

Oral administration of butorphanol caused a significant increase in themechanical allodynia withdrawal threshold and cold allodynia withdrawalthreshold in rats with neuropathic pain in comparison to the controlreadings. This effect of butorphanol was observed to be dependent of thedose. Thus, butorphanol demonstrated a marked dose dependent effect inrats with vincristine induced neuropathy.

Example 63 Aim

The aim of this study was to evaluate the effect of oral administrationof butorphanol in rats with paclitaxel induced painful neuropathy. Theprimary measurements were made mechanical and thermal allodynia designedto detect effects of the treatment(s) on neuropathic pain.

Animals:

Wistar rats weighing 250±20 g were maintained on standard laboratorydiet and having free access to tap water ad lib were employed in thepresent study. They were housed in the animal house and were exposed to12 hr cycle of light and dark. The experiments were conducted in asemi-sound proof laboratory. Care of the animals was in accordance withguidelines for experimentation on animals.

Experimental Design:

Rats were injected on five alternate days (day 4, 6, 8, 10 & 12) withpaclitaxel (2 mg/kg i.p.) using an injection volume of 2 ml/kg. Thus,the cumulative dose of paclitaxel was computed to be 10 mg/kg. Teststook place ten days after the last injection and continued over the nextthree weeks. Five groups were employed in the present study with eachgroup comprising of 8 animals: Group I (Vehicle control group): Vehicle(2 ml/kg, i.p) administration was followed by the pain assessment; GroupII (Oral butorphanol treatment group-I): Butorphanol (0.01 mg/kg, p.o.)administration was followed by the pain assessment; Group III (Oralbutorphanol treatment group-II): Butorphanol (0.03 mg/kg, p.o.)administration was followed by the pain assessment; Group IV (Oralbutorphanol treatment group-III): Butorphanol (0.1 mg/kg, p.o.)administration was followed by the pain assessment; Group V (Oralbutorphanol treatment group-IV): Butorphanol (0.3 mg/kg, p.o.)administration was followed by the pain assessment.

Measurement of Effect

Assessment of Mechanical Allodynia

Mechano-allodynia was assessed using von Frey filaments. The filamentsare nylon monofilaments of different diameters that exert defined levelsof force to cause the hair to bend. Once a rat was calm, a series of vonFrey filaments with roughly exponential incremental target force (0.008,0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1, 1.4, 2, 4, 6, 8, 10, 15, 26, 60,100, 180, 300 g) were applied to the bottom of the right paw, behind thefront pads and lateral to the medial pads of the rat. The filament waspresented perpendicular to the rat paw and applied with enough force soas to cause a slight bend. It was held steadily against the paw for aperiod of 5 s. A response was considered positive if, within the 5-speriod, the rat withdrew from the stimulus or briskly withdrewimmediately after the filament was removed. A negative response was theone in which the rat did not withdraw within the given time. Testing wasinitiated using middle filament (2 g). A negative response required theuse of next filament with greater bending force. A positive responserequired the use of next filament with less bending force. Both hindpaws were tested for allodynia and the average of the two was recordedas data. Results were expressed in grams and determined before and 30and 60 min after the administration of the test drugs.

Assessment of Cold Allodynia

For the assessment of cold allodynia, which was stable for 3 weeks, therats were placed on a wire mesh covered with a plastic dome and wereallowed to habituate until the exploratory behavior diminished. Coldallodynia was measured as the number of foot withdrawal responses afterapplication of stimuli to the plantar surface of the paw. A drop ofacetone (10 μl) was gently applied to the heel of the animal with amicro-pipette. A brisk foot withdrawal response (shaking, tapping, orlicking) after the spread of acetone over the plantar region of the pawwas considered a sign of cold allodynia. Acetone was applied two times(once every 5 min) on the left paw, and the number of reactions(shaking, tapping, or licking) was counted during 30 sec. A cut-offnumber of reactions were fixed at 20 per trial (i.e. 40). The score wasexpressed as accumulated numbers of reactions over the trials anddetermined before and 30 and 60 min after administration of the testdrugs. Each individual test was expressed as a percentage of maximumpossible effect (% MPE):

${M\; P\;{E(\%)}} = {\frac{\left( {{{Post}\mspace{20mu}{treatment}\mspace{14mu}{frequency}} - {{pre}\mspace{14mu}{treatment}\mspace{14mu}{latency}}} \right)}{\left( {{{Cut}\text{-}{off}\mspace{14mu}{frequency}} - {{pre}\mspace{14mu}{treatment}\mspace{14mu}{latency}}} \right)} \times 100}$

The peak effect was seen at a time point 30 minutes after the drugadministration. MPE (%) at 30 min time point was employed as aquantitative measure of the analgesic effect of the test drugs.

Data Analysis:

The anti-nociceptive effect was plotted assessed having time (relativeto dosing time point) on the x-axis and percent maximum possible effect(% MPE) on the y-axis. The results were expressed as mean±standard errorof means (S.E.M.). Statistical analysis for was done using one-wayANOVA, followed by Tukey's multiple range tests as post-hoc analysis. Avalue of P<0.05 was considered to be statistically significant.

Results

Response to Mechanical Allodynia

Baseline mean mechanical withdrawal threshold in the paclitaxeltreatment induced neuropathic rat was observed to be 4.23±0.42 g. Allanimals included in the study had a mean threshold below five, thusconforming to the requirements of being considered neuropathic. Oraladministration of butorphanol demonstrated a dose dependent increase inthe mechanical withdrawal threshold that elicits pain in the neuropathicrats. Moreover, the effect of the butorphanol was dependent on the doseand the peak effect of drug was noted to be 30 min post-administration(FIG. 17).

Response to Cold Allodynia

Baseline of cold allodynia score was determined using the acetone droptest in the paclitaxel treatment induced neuropathic rats. Moreover,effect of the drug was dependent on the dose and the peak effect of drugwas noted to be 30 min post-administration. Furthermore, the oraladministration of butorphanol demonstrated a dose dependent decrease inthe cold allodynia score in the neuropathic rats (FIG. 18).

Conclusion

Oral administration of butorphanol caused a significant increase in themechanical allodynia withdrawal threshold and cold allodynia withdrawalthreshold in rats with neuropathic pain in comparison to the controlreadings. This effect of butorphanol was observed to be dependent of thedose. Thus, butorphanol demonstrated a marked dose dependent effect inrats with paclitaxel induced neuropathy.

Streptozotocin Induced Diabetic Neuropathy Example 64 Aim

The aim of this study was to evaluate the effect of oral administrationof butorphanol in rats with streptozotocin (STZ) induced diabetesneuropathy. A single injection of streptozotocin (STZ) (40-70 mg/kg,i.p.) was used to induce diabetes in rats. The primary measurements weremade mechanical and thermal allodynia designed to detect effects of thetreatment(s) on neuropathic pain.

Animals:

Wistar rats weighing 250±20 g were maintained on standard laboratorydiet and having free access to tap water ad lib were employed in thepresent study. They were housed in the animal house and were exposed to12 hr cycle of light and dark. The experiments were conducted in asemi-sound proof laboratory. Care of the animals was in accordance withguidelines for experimentation on animals.

Experimental Design:

The STZ-induced diabetes model was adapted from Arison et al (1967). Onthe experimental day 1 all rats were fasted 6-8 hrs prior to STZtreatment. Immediately prior to the injection, STZ was dissolved in 50Mm sodium citrate buffer (pH 4.5) to a final concentration of 10 mg/ml.Using an insulin syringe and a 26 G needle, STZ solution was injectedintraperitoneally at a dose level of 40-70 mg/kg. The animals were thenshifted individually to their home cage and were provided normal foodand 10% sucrose water. On experimental day 2 the sucrose water wasswitched to regular water. On experimental day 21 all rats were fastedfor 6-8 hrs the blood glucose level was tested from a tail vein sampleusing a spectrophotometeric method in order to check hyperglycemia.Blood glucose levels ranging from 250-600 mg/dL confirmed diabetes inthe STZ injected rats. Neuropathy assessment tests were performed afterthe completion of 8 weeks after STZ treatment. Tests continued over thenext four weeks. Five groups were employed in the present study witheach group comprising of 8 animals: Group I: Vehicle control group, 2ml/kg, i.p.; Group II: Oral butorphanol, 1 mg/kg; Group III: Oralbutorphanol 3 mg/kg; Group IV: Oral butorphanol 10 mg/kg; Group V: Oralbutorphanol 30 mg/kg.

Measurement of Effect

Assessment of Mechanical Allodynia:

Mechano-allodynia was assessed using von Frey filaments. The filamentsare nylon monofilaments of different diameters that exert defined levelsof force to cause the hair to bend. Once a rat was calm, a series of vonFrey filaments with roughly exponential incremental target force (0.008,0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1, 1.4, 2, 4, 6, 8, 10, 15, 26, 60,100, 180, 300 g) were applied to the bottom of the right paw, behind thefront pads and lateral to the medial pads of the rat. The filament waspresented perpendicular to the rat paw and applied with enough force soas to cause a slight bend. It was held steadily against the paw for aperiod of 5 s. A response was considered positive if, within the 5-speriod, the rat withdrew from the stimulus or briskly withdrewimmediately after the filament was removed. A negative response was theone in which the rat did not withdraw within the given time. Testing wasinitiated using middle filament (2 g). A negative response required theuse of next filament with greater bending force. A positive responserequired the use of next filament with less bending force. Both hindpaws were tested for allodynia and the average of the two was recorded.Results were expressed in grams and determined before and 30 and 60 minafter the administration of the test drugs.

Assessment of Cold Allodynia

For the assessment of cold allodynia, which was stable for 3 weeks, therats were placed on a wire mesh covered with a plastic dome and wereallowed to habituate until the exploratory behavior diminished. Coldallodynia was measured as the number of foot withdrawal responses afterapplication of stimuli to the plantar surface of the paw. A drop ofacetone (10 μl) was gently applied to the heel of the animal with amicro-pipette. A brisk foot withdrawal response (shaking, tapping, orlicking) after the spread of acetone over the plantar region of the pawwas considered a sign of cold allodynia. Acetone was applied two times(once every 5 min) on the left paw, and the number of reactions(shaking, tapping, or licking) was counted during 30 sec. A cut-offnumber of reactions were fixed at 20 per trial (i.e. 40). The score wasexpressed as accumulated numbers of reactions over the trials anddetermined before and 30 and 60 min after administration of the testdrugs. Each individual test was expressed as a percentage of maximumpossible effect (% MPE):

${M\; P\;{E(\%)}} = {\frac{\left( {{{Post}\mspace{20mu}{treatment}\mspace{14mu}{frequency}} - {{pre}\mspace{14mu}{treatment}\mspace{14mu}{frequency}}} \right)}{\left( {{{Cut}\text{-}{off}\mspace{14mu}{frequency}} - {{pre}\mspace{14mu}{treatment}\mspace{14mu}{frequency}}} \right)} \times 100}$

The peak effect was seen at a time point 30 minutes after the drugadministration. MPE (%) at 30 min time point was employed as aquantitative measure of the analgesic effect of the test drugs.

Data Analysis:

The anti-nociceptive effect was plotted assessed having time (relativeto dosing time point) on the x-axis and percent maximum possible effect(% MPE) on the y-axis. The results were expressed as mean±standard errorof means (S.E.M.). Statistical analysis for was done using one-wayANOVA, followed by Tukey's multiple range tests as post-hoc analysis. Avalue of P<0.05 was considered to be statistically significant.

Results

Response to Mechanical Allodynia

Baseline mean mechanical withdrawal threshold in the diabetes inducedneuropathy in rats was observed to be 2.91±0.23 g. All animals includedin the study had a mean threshold below five, thus conforming to therequirements of being considered neuropathic. Oral administration ofbutorphanol demonstrated a dose dependent increase in the mechanicalwithdrawal threshold that elicits pain in the neuropathic rats.Moreover, the effect of the butorphanol was dependent on the dose andthe peak effect of drug was noted to be 30 min post-administration (FIG.19).

Response to Cold Allodynia

Baseline of cold allodynia score was determined using the acetone droptest in the SNL induced neuropathic rats. Moreover, effect of the drugwas dependent on the dose and the peak effect of drug was noted to be 30min post-administration. Furthermore, the oral administration ofbutorphanol demonstrated a dose dependent decrease in the cold allodyniascore in the neuropathic rats (FIG. 20).

Conclusion

Oral administration of butorphanol caused a significant increase in themechanical allodynia and cold allodynia withdrawal thresholds in ratswith STZ induced diabetic neuropathic pain in comparison to the controlreadings. This effect of butorphanol was observed to be dependent of thedose. Thus, butorphanol demonstrated a marked dose dependent effect inrats with STZ induced diabetic neuropathic pain.

Clinical Response to Modified Release Butorphanol Example 65

The therapeutic effect of single dose oral butorphanol was evaluated inpatients with chronic pain. Oral butorphanol intended for delayed onset,rapid release was prepared by encapsulating butorphanol tartrate 6 mgdiluted with 94 mg of lactose) into a capsule.

Following encapsulation, the dosage form was coated using the coatedwith polymers using the method described herein to provide release at apH≧7. Release of capsule contents at the desired pH was confirmed by invitro testing, using a dye. Five subjects each with chronic low backpain and osteoarthritis, all with moderate to severe pain received asingle dose of oral delayed onset, rapid release butorphanol early inthe morning. The onset of pain and magnitude of pain relief was recordedusing a categorical scale ((My relief from starting pain is: 0=None, 1=Alittle, 2=Some, 3=A lot, and 4=Complete). After a delay of approximately2 to 5 hours, 3 of 5 patients with back pain and 4 of 5 patients withosteoarthritis reported some a lot of relief or complete relief. Onepatient with osteoarthritis reported some relief. One patient with lowback pain reported a lot relief after one hour and a further one patientreported little relief. Two patients each experienced mild nausea andmild drowsiness at the time of their pain relief

Example 66

The therapeutic effect of repeated dose oral butorphanol was evaluatedin patients with chronic pain by comparing oral immediate releasebutorphanol with oral modified release butorphanol intended for delayedonset, rapid release butorphanol. Oral immediate release butorphanol wasprepared by encapsulating butorphanol tartrate 4 mg diluted with 96 mgof lactose) into a capsule. Oral butorphanol intended for delayed onset,rapid release was prepared by coating the above capsules with polymers,using the method described herein to provide release at a pH≧7. Releaseof capsule contents at the desired pH was confirmed by in vitro testing,using a dye at pH 5.5 and at pH 7. Oral butorphanol intended forimmediate release liberated the dye at pH 5.5 in less than 10 minutes,while oral butorphanol intended for delayed onset, rapid release did notliberate its dye at pH 5.5 for at least 2 hours, but liberated its dyeat pH 7 in less than 10 minutes. Five patients each with chronic lowback pain and osteoarthritis, all with moderate to severe pain receivedoral immediate release butorphanol or delayed onset, rapid releasebutorphanol for one week (5 to 7 days). Patients were instructed to takethe first dose of medication at bedtime. Pain was assessed in the clinicbefore initiating therapy and upon the return clinic visit one weeklater using an 11-point Likert Numeric Rating Scale (NRS). Side effectswere recorded at the return clinic visit using a non-directedquestionnaire. Both oral immediate release butorphanol and delayedonset, rapid release butorphanol provided pain relief. However, the painrelief in the overall treatment group receiving delayed onset, rapidrelease was greater (Baseline Score: 7.6, Post-treatment Score 3.0) thanafter oral immediate release butorphanol (Baseline Score: 7.2,Post-treatment Score 4.6). Nausea and drowsiness were almost twice ascommon in the immediate release butorphanol than in the delayed onset,rapid release butorphanol group. In addition, the intensity of bothnausea and drowsiness was higher in the immediate release butorphanolthan in the delayed onset, rapid release butorphanol group.

These and other embodiments of the present invention will readily occurto those of ordinary skill in the art in view of the disclosure herein.

The included examples are illustrative but not limiting of the methodsand composition of the present invention. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered and obvious to those skilled in the art are within thespirit and scope of the invention.

A wide variety of materials can be used for preparing the dosage formaccording to this invention. This invention therefore contemplates theuse of materials other than those specifically disclosed herein,including those which may hereafter become known to the art to becapable of performing the necessary functions. In all instances whereinprophetic examples are provided, these compositions are intended to beexemplary and it should be understood that the specific procedures,constituents, amounts thereof and the like can be varied in order toobtain a composition possessing desired properties.

Having now fully described the invention, it will be understood to thoseof ordinary skill in the art that the same can be performed within awide and equivalent range of conditions, formulations, and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents and publications cited herein are fullyincorporated by reference herein in their entirety.

What is claimed is:
 1. An oral dosage form comprising: (i) atherapeutically effective amount of butorphanol, a pharmaceuticallyacceptable salt thereof, or a mixture thereof, and (ii) controlledrelease material to render said dosage form suitable for modifiedrelease of the butorphanol in a therapeutically effective mannerfollowing oral administration of the dosage form, wherein the dosageform provides first release of butorphanol in an anatomic regionselected from the group consisting of the duodenum, the jejunum, theileum, and the colon.
 2. The oral dosage form of claim 1, wherein thedosage form provides first release of butorphanol not earlier than twohours following ingestion of the dosage form.
 3. The oral dosage form ofclaim 1, wherein the dosage form provides first release of butorphanolnot earlier than three hours following ingestion of the dosage form. 4.The oral dosage form of claim 1, wherein the dosage form provides firstrelease of butorphanol not earlier than four hours following ingestionof the dosage form.
 5. The oral dosage form of claim 1, wherein thedosage form provides first release of butorphanol from the dosage format a pH not less than 5 after oral administration.
 6. The oral dosageform of claim 1, wherein the dosage form provides first release ofbutorphanol from the dosage form at a pH not less than 6 after oraladministration.
 7. The oral dosage form of claim 1, wherein the dosageform provides first release of butorphanol from the dosage form at a pHnot less than 6.5 after oral administration.
 8. The oral dosage form ofclaim 1, wherein the dosage form provides first release of butorphanolfrom the dosage form at a not less than 6.8 after oral administration.9. The oral dosage form of claim 1, wherein the dosage form releasessubstantially all of the butorphanol to one or both of the ileum and thecolon following oral administration of the dosage form.
 10. The oraldosage form of claim 1, wherein the dosage form releases substantiallyall of the butorphanol to the colon following oral administration of thedosage form.
 11. The oral dosage form of claim 1, wherein the dosageform releases butorphanol for at least six hours post ingestion.
 12. Theoral dosage form of claim 1, wherein the dosage form releasesbutorphanol for at least 12 hours post ingestion.
 13. The oral dosageform of claim 1, wherein the dosage form releases butorphanol for atleast 24 hours post ingestion.
 14. The oral dosage form of claim 1,wherein the dosage form releases a therapeutically effective amount ofbutorphanol for at least 12 hours post ingestion.
 15. The oral dosageform of claim 1, wherein the dosage form releases a therapeuticallyeffective amount of butorphanol for at least 18 hours post ingestion.16. The oral dosage form of claim 1, wherein the dosage form releases atherapeutically effective amount of butorphanol for at least 24 hourspost ingestion.
 17. The oral dosage form of claim 1, wherein the dosageform exhibits reduced psychic effects in recreational drug users whencompared with a dosage form of butorphanol selected from the groupconsisting of intranasal, oral immediate release, and oral extendedrelease dosage forms.
 18. A method of deterring abuse and misuse ofbutorphanol, the method comprising orally administering (i) atherapeutically effective amount of butorphanol, a pharmaceuticallyacceptable salt thereof, or a mixture thereof, admixed with (ii)controlled release material to render the dosage form suitable formodified release, wherein the dosage form provides first release ofbutorphanol in an anatomic region selected from the group consisting ofthe duodenum, the jejunum, the ileum, and the colon.
 19. A method ofimproving treatment compliance in a subject in need of treatment withbutorphanol, the method comprising orally administering (i) atherapeutically effective amount of butorphanol, a pharmaceuticallyacceptable salt thereof, or a mixture thereof, admixed with (ii)controlled release material to render the dosage form suitable formodified release, wherein the dosage form provides first release ofbutorphanol in an anatomic region selected from the group consisting ofthe duodenum, the jejunum, the ileum, and the colon.